Devices for controlling magnetic nanoparticles to treat fluid obstructions

ABSTRACT

A system for the physical manipulation of free magnetic rotors in a circulatory system using a remotely placed magnetic field-generating stator is provided. In one embodiment, the invention relates to the control of magnetic particles in a fluid medium using permanent magnet-based or electromagnetic field-generating stator sources. Such a system can be useful for increasing the diffusion of therapeutic agents in a fluid medium, such as a human circulatory system, which can result in substantial clearance of fluid obstructions, such as vascular occlusions, in a circulatory system resulting in increased blood flow. Examples of vascular occlusions targeted by the system include, but are not limited to, atherosclerotic plaques, including fibrous caps, fatty buildup, coronary occlusions, arterial stenosis, restenosis, vein thrombi, arterial thrombi, cerebral thrombi, embolisms, hemorrhages, other blood clots, and very small vessels.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/155,386 filed May 16, 2016, now U.S. Pat. No. 10,029,008, which is acontinuation of U.S. patent application Ser. No. 14/268,244 filed May 2,2014, now issued as U.S. Pat. No. 9,339,664, which is a continuation ofU.S. patent application Ser. No. 13/505,447 having a 371(c) date of Aug.21, 2012, now issued as U.S. Pat. No. 8,715,150, which is a NationalPhase application of International Application Number PCT/US2010/055133filed Nov. 2, 2010, published as International Publication Number WO2011/053984 on May 5, 2011, which claims priority to U.S. ProvisionalApplication Ser. No. 61/280,321 filed on Nov. 2, 2009, each of which isincorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

FIELD

The present invention relates to a system for the physical manipulationof free magnetic rotors in a circulatory system using a remotely placedmagnetic field-generating stator.

INTRODUCTION

The treatment of fluid obstructions in the circulatory system, includingvascular occlusions in vessels of the brain and vessels of theextremities, has included the use of drugs that can dissolve theobstructions and obstruction removal devices, e.g., thrombectomydevices. However, side-effects of such drugs are difficult to controland such obstruction removal devices often involve invasive proceduresthat cause unintended or secondary tissue damage. Both the use of drugsat normal dosages and the use of thrombectomy devices can cause death.

The management of magnetic fluids is a field that has had considerableattention and effort, but with limited success in medicine. A textbook“Ferrohydro-Dynamics,” R. E. Rosensweig, Dover Publications, New York,1985, provides a useful background of the physics of magnetic particlesin fluids, but with virtually no coverage of applications in medicine.In the medical field, magnetic forces are used commercially tomanipulate and navigate catheters and guide wires in arteries (e.g.,Stereotaxis, Inc., St Louis, Mo.; and Magnetecs, Inc., Santa Monica,Calif.). However, such invasive techniques can cause unintended orsecondary tissue damage as mentioned above. In addition, very-lowfrequency rotational magnetic fields have been used to navigate andorient magnetically-enabled gastro-intestinal “pillcams.” Although theuse of magnetic nanoparticles has been proposed for magnetic resonanceimaging contrast enhancement, tissue repair, immunoassays,detoxification of biological fluids, hyperthermia, drug delivery and incell separation in the circulatory system, such uses have failed toovercome the difficulty of targeted delivery of the drug in areas of lowblood flow, or total blockage because of the small magnetic moment ofsuch nanoparticles. In other instances, magnetic nanoparticles have beenconjugated to compounds, such as antibodies, that specifically bind tocertain cell types or occlusions in the circulatory system, but the useof such targeting methods in a low blood flow or blocked circulatorysystem have not succeeded.

Therefore, what is needed are new devices and methods of treating fluidobstructions by increasing the safety of drug delivery and reducing theuse of invasive surgical entry.

SUMMARY

A therapeutic system is provided comprising (a) a magnet having amagnetic field and a gradient for controlling magnetic rotors in acirculatory system, and (b) a controller for positioning and rotatingthe field and the gradient in a manner to agglomerate and traverse themagnetic rotors with respect to a therapeutic target in the circulatorysystem. Using the therapeutic system, contact of the therapeutic targetwith a pharmaceutical composition in the circulatory system isincreased. In various aspects, the pharmaceutical composition can beattached to the magnetic rotor, and in other aspects can be administeredto the circulatory system separate from the magnetic rotors. In certaininstances, the pharmaceutical composition can be a thrombolytic drug.

Therapeutic targets of the system can include fluid obstructions such asatherosclerotic plaques, fibrous caps, fatty buildup, coronaryocclusions, arterial stenosis, arterial restenosis, vein thrombi,arterial thrombi, cerebral thrombi, embolism, hemorrhage and very smallvessels. In various aspects, the circulatory system is vasculature of apatient, in particular a human patient.

In various embodiments, the therapeutic system comprises a permanentmagnet coupled to a motor, and the controller controls a motor toposition the magnet at an effective distance, an effective plane withrespect to the therapeutic target, and rotates the magnet at aneffective frequency with respect to the therapeutic target. In variousembodiments, the therapeutic system comprises an electromagnet having amagnetic field strength and magnetic field polarization driven byelectrical current, and the controller positions the electromagnet at aneffective distance, an effective plane with respect to the therapeutictarget, and rotates the magnetic field of the electro-magnet byadjusting the electrical current.

The therapeutic system can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, such that a user controls the magneticrotors to clear the therapeutic target by adjusting a frequency of therotating magnetic field, a plane of the rotating magnetic field withrespect to the therapeutic target, and a distance of the rotatingmagnetic field with respect to the therapeutic target. In variousaspects, the therapeutic target can be a thrombosis in a human bloodvessel. In various aspects, the magnetic rotors can be magneticnanoparticles injected into the circulatory system.

In various aspects of the invention, the magnetic rotors traversethrough the fluid in the circular motion by repeatedly (a) walking endover end along the blood vessel away from the magnetic field in responseto the rotation of the rotors and an attractive force of the magneticfield, and (b) flowing back through the fluid towards the magnetic fieldin response to the rotation of the rotors and the attractive force ofthe magnetic field.

In yet another embodiment, a therapeutic system is provided forincreasing fluid flow in a circulatory system comprising a magnet havinga magnetic field for controlling a magnetic tool in the fluid, and acontroller positioning and rotating the magnetic field with respect tothe therapeutic target to rotate an abrasive surface of the magnetictool and maneuver the rotating abrasive surface to contact and increasefluid flow through or around the therapeutic target. In various aspects,the circulatory system can be vasculature of a patient, particularly ahuman patient. In various aspects, the magnetic tool can be coupled to astabilizing rod, and the magnetic tool rotates about the stabilizing rodin response to the rotating magnetic field. In yet another aspect, themagnetic tool can include an abrasive cap affixed to a magnet whichengages and cuts through the therapeutic target. In another aspect, thecontroller positions the magnetic tool at a target point on thetherapeutic target, and rotates the magnetic tool at a frequencysufficient to cut through the therapeutic target. The magnet can bepositioned so that poles of the magnet periodically attract the opposingpoles of the magnetic tool during rotation, the magnetic tool is pushedtowards the therapeutic target by a stabilizing rod upon which themagnetic tool rotates. In another aspect, the magnet can be positionedso that the poles of the magnet continuously attract the opposing polesof the magnetic tool during rotation, and the magnetic tool is pulledtowards the therapeutic target by an attractive force of the magnet.

In another embodiment, a system is provided for increasing fluid flow ina circulatory system comprising a magnet having a magnetic field forcontrolling magnetic rotors in the fluid, a display for displaying, to auser, the magnetic rotors and the therapeutic target in the fluid, and acontroller, in response to instructions from the user, controlling themagnetic field to: (a) position the magnetic rotors adjacent to thetherapeutic target, (b) adjust an angular orientation of the magneticrotors with respect to the therapeutic target, and (c) rotate andtraverse the magnetic rotors through the fluid in a circular motion tomix the fluid and substantially clear the therapeutic target.

In various aspects, the display can display real time video of themagnetic rotors and the therapeutic target, and the display cansuperimpose a graphic representative of a rotation plane of the magneticfield and another graphic representative of the attractive force of themagnetic field on the real time video. In another aspect, the magnet canbe a permanent magnet coupled to a motor and a movable arm, and thecontroller can include a remote control device for a user to manipulatethe position, rotation plane and rotation frequency of the magneticfield with respect to the therapeutic target.

In another aspect, the display can adjust the graphics in response toinstructions given by the user through the remote control device. Invarious aspects, the magnet can be an electro-magnet coupled to a motorand a movable arm, and the controller can perform image processing toidentify the location, shape, thickness and density of the therapeutictarget, and automatically manipulates the movable arm to control theposition, rotation plane and rotation frequency of the magnetic field toclear the therapeutic target.

In yet another aspect, the magnetic rotors can be formed by magneticnanoparticles which combine in the presence of the magnetic field. Inanother aspect, the fluid can be a mixture of blood and a thrombolyticdrug, the blood and thrombolytic drug being mixed by the circular motionof the magnetic rotors to erode and clear the therapeutic target. In yetanother aspect, the circular motion of the magnetic rotors can redirectthe thrombolytic drug from a high flow blood vessel to a low flow bloodvessel which contains the therapeutic target.

A method is also provided for increasing fluid flow in a circulatorysystem comprising: (a) administering a therapeutically effective amountof magnetic rotors to the circulatory system of a patient in needthereof, and (b) applying a magnet to the patient, the magnet having amagnetic field and a gradient for controlling the magnetic rotors in acirculatory system, and (c) using a controller for positioning androtating the field and the gradient in a manner to agglomerate andtraverse the magnetic rotors with respect to a therapeutic target in thecirculatory system of the patient, wherein contact of the therapeutictarget with a pharmaceutical composition in the circulatory system isincreased and fluid flow is increased.

In various aspects, the pharmaceutical composition can be attached tothe magnetic rotor. In other aspects, the pharmaceutical composition canbe administered to the circulatory system of the patient separate fromthe magnetic rotors. In various embodiments, the pharmaceuticalcomposition is a thrombolytic drug.

In various aspects, therapeutic target can be a fluid obstruction suchas atherosclerotic plaques, fibrous caps, fatty buildup, coronaryocclusions, arterial stenosis, arterial restenosis, vein thrombi,arterial thrombi, cerebral thrombi, embolism, hemorrhage and very smallvessel. In yet another aspect, the circulatory system is vasculature ofa patient, particularly a human patient.

In yet another aspect, the magnet can be a permanent magnet coupled to amotor, and the controller can control a motor to position the magnet atan effective distance, an effective plane with respect to thetherapeutic target, and rotates the magnet at an effective frequency. Inanother aspect, the magnet can be an electromagnet having a magneticfield strength and magnetic field polarization driven by electricalcurrent, and the controller can position the electromagnet at aneffective distance, an effective plane with respect to the therapeutictarget, and rotates the magnetic field of the electro-magnet byadjusting the electrical current.

The system of the method can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, wherein a user controls the magneticrotors to increase contact of the therapeutic target with apharmaceutical composition in the circulatory system by adjusting afrequency of the rotating magnetic field, a plane of the rotatingmagnetic field with respect to the therapeutic target, and a distance ofthe rotating magnetic field with respect to the therapeutic target.

In various aspects, the therapeutic target can be a thrombosis in ahuman blood vessel. In another aspect, the magnetic rotors can bemagnetic nanoparticles injected into the circulatory system. Inparticular, the therapeutic target is a full or partial blockage of avein bivalve. In yet another aspect, the magnetic rotors traversethrough the fluid in the circular motion by repeatedly (a) walking endover end along the blood vessel away from the magnetic field in responseto the rotation of the rotors and an attractive force of the magneticfield, and (b) flowing back through the fluid towards the magnetic fieldin response to the rotation of the rotors and the attractive force ofthe magnetic field.

In various aspects, the rotor is a magnetic nanoparticle of a diameterfrom about 20 nm to about 60 nm. In another aspect, the therapeutictarget is a vascular occlusion in the patient head or a vascularocclusion in the patient leg.

In yet another embodiment, a method is provided for increasing drugdiffusion in a circulatory system comprising (a) administering atherapeutically effective amount of magnetic rotors to the circulatorysystem of a patient in need thereof, and (b) applying a magnet to thepatient, the magnet having a magnetic field and a gradient forcontrolling the magnetic rotors in a circulatory system, and (c) using acontroller for positioning and rotating the field and the gradient in amanner to agglomerate and traverse the magnetic rotors with respect to atherapeutic target in the circulatory system of the patient, whereindiffusion of a pharmaceutical composition in the circulatory system atthe therapeutic target is increased.

In various aspects, the pharmaceutical composition can be attached tothe magnetic rotor. In other aspects, the pharmaceutical composition canbe administered to the circulatory system of the patient separate fromthe magnetic rotors. In various embodiments, the pharmaceuticalcomposition is a thrombolytic drug.

In various aspects, therapeutic target can be a fluid obstruction suchas atherosclerotic plaques, fibrous caps, fatty buildup, coronaryocclusions, arterial stenosis, arterial restenosis, vein thrombi,arterial thrombi, cerebral thrombi, embolism, hemorrhage and very smallvessel. In yet another aspect, the circulatory system is vasculature ofa patient, particularly a human patient.

In yet another aspect, the magnet can be a permanent magnet coupled to amotor, and the controller can control a motor to position the magnet atan effective distance, an effective plane with respect to thetherapeutic target, and rotates the magnet at an effective frequency. Inanother aspect, the magnet can be an electromagnet having a magneticfield strength and magnetic field polarization driven by electricalcurrent, and the controller can position the electromagnet at aneffective distance, an effective plane with respect to the therapeutictarget, and rotates the magnetic field of the electro-magnet byadjusting the electrical current.

The system of the method can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, wherein a user controls the magneticrotors to increase contact of the therapeutic target with apharmaceutical composition in the circulatory system by adjusting afrequency of the rotating magnetic field, a plane of the rotatingmagnetic field with respect to the therapeutic target, and a distance ofthe rotating magnetic field with respect to the therapeutic target.

In various aspects, the therapeutic target can be a thrombosis in ahuman blood vessel. In another aspect, the magnetic rotors can bemagnetic nanoparticles injected into the circulatory system. Inparticular, the therapeutic target is a full or partial blockage of avein bivalve. In yet another aspect, the magnetic rotors traversethrough the fluid in the circular motion by repeatedly (a) walking endover end along the blood vessel away from the magnetic field in responseto the rotation of the rotors and an attractive force of the magneticfield, and (b) flowing back through the fluid towards the magnetic fieldin response to the rotation of the rotors and the attractive force ofthe magnetic field.

In various aspects, the rotor is a magnetic nanoparticle of a diameterfrom about 20 nm to about 60 nm. In another aspect, the therapeutictarget is a vascular occlusion in the patient head or a vascularocclusion in the patient leg.

These and other features, aspects and advantages of the presentteachings will become better understood with reference to the followingdescription, examples and appended claims.

DRAWINGS

Those of skill in the art will understand that the drawings, describedbelow, are for illustrative purposes only. The drawings are not intendedto limit the scope of the present teachings in any way.

FIGS. 1A and 1B show an example of a permanent-magnet stator systemwhose magnet's North-South pole rotates in a plane parallel to thesystem's front face, which is driven by a single motor.

FIG. 2 shows a portable positioner cart to which the magnet system ofFIG. 1 is attached.

FIG. 3 shows an example of a permanent-magnet stator system whosemagnet's North-South pole rotates in a plane perpendicular to thesystem's front face, which is driven by a single motor.

FIGS. 4A and 4B (cross-section of 4A) show an example of apermanent-magnet stator system driven by two motors, allowing the magnetto be rotated in any plane.

FIG. 5 shows an example of a three-electromagnet stator system, withpower supplies, attached to an arm positioner.

FIGS. 6A to 6C show an example of a user control interface for amagnetic stator system.

FIG. 7 shows an algorithm example that will allow a user to define afield rotation in space for the wireless control of magnetic rotors.

FIG. 8A shows the manipulation of magnetic particles to create motion.FIG. 8B details the action of the magnetic field on a magnetic particleto create rotation. FIG. 8C illustrates the magnetic manipulation of amagnetic particle distribution inside a fluid-filled enclosure to createflow patterns. FIG. 8D shows the magnetic manipulation of a magneticparticle distribution to amplify the effects of clot-busting drugs on aclot.

FIG. 9 illustrates the manipulation of a magnet to cross a vesselocclusion.

FIGS. 10A and 10B illustrate the use of the magnetomotive stator systemand magnetic nanoparticles for the treatment of a vascular occlusion inthe brain.

FIGS. 11A-E illustrate a model for the enhanced diffusion ofpharmaceutical compounds in an area of complete blockage having no fluidflow, where (A) shows a vessel having no drug, (B) shows the addition ofa drug to the system (grey), but the inability to mix at the site of theblockage, (C) the addition of magnetic nanoparticles to the system anddrawn to the blockage site via magnet (not shown), (D) turbulencecreated by applying the magnetic field and gradient in a time-dependentfashion and mixing the drug to come closer to contacting the blockagesite, and (E) showing completed diffusion of the drug and contact at theblockage site via mixing using the magnetic nanoparticles.

FIG. 12 is a drawing of the magnetic system that is a first preferredembodiment of this invention.

FIG. 13 is a drawing of the magnetic system that is a second preferredembodiment of this invention.

FIG. 14A is a cross sectional drawing displaying a representativetargeted region of a blocked lumen with no flow, under conventionaltreatment.

FIG. 14B is a cross sectional drawing of a targeted region having bloodflow, but with ineffective drug clearance using standard drug delivery.

FIGS. 15A-15C show arranged structuring of magnetic nanoparticles tocreate rods as used in procedures with the present invention, where (A)shows unorganized nanoparticles in zero field, (B) shows a small fieldapplied to the nanoparticles and organization into “rods,” and (C) showsa larger field applied to the nanoparticles.

FIG. 16 is a plot of nanoparticle agglomerate rod length as a functionof the applied magnetic field, showing a limiting length.

FIGS. 17A-17H depict a sequence of end over end motions leading totranslation of the magnetic particle.

FIGS. 18A and 18B show the characteristic saturation of particles withincreased density as a result of rotating motion leading to a buildup ofmagnetic particles.

FIGS. 19A and 19B support a derivation of the physics of elements andfields leading to magnetic torque on a nanoparticle rod of thisinvention.

FIG. 19C describes the distribution of kinetic energy as a function offrequency of rotation of the rods.

FIG. 20A shows the introduction of turbulence with spinning rods in avessel with no flow, to treat the occlusion problem shown in FIG. 14A.

FIG. 20B exhibits motion and effect of drug delivery according to thisinvention for introduction of turbulence in the occluded flow categoryshown in FIG. 14B.

FIG. 21A is a cross section view of a group of rotating rods in circularmotion against a total occlusion in a vessel.

FIG. 21B is a cross section view of the rotation of rods starting toform a ball.

FIG. 21C is a cross section view of the rotating ball of rods and clotmaterial having completely opened the obstructed vein.

FIG. 21D is a cross section view of the ball of FIG. 21C being removedby a small magnet on a guide wire.

FIG. 22 is a cross section view of a vessel with rotating magneticcarriers applying drugs to safely remove occluding material on a valveleaflet in a blood vessel.

FIG. 23 exhibits the result of end over end motion of a magnetic rod“walk” along a path to a distant clot in a complex vessel.

FIGS. 24A and 24B exhibit the generation of motion of amagnetically-enabled thrombectomy device which is depicted as a sphere,where (A) shows no field or gradient applied and (B) shows a field andgradient applied causing the sphere to traverse laterally.

FIG. 25A is a cross section view of a rotating magnetically-enabledthrombectomy sphere in circular motion against a total occlusion in avessel.

FIG. 25B is a cross section view of the magnetically-enabledthrombectomy sphere wearing away the surface of the occlusion.

FIG. 25C is a cross section view of the magnetically-enabledthrombectomy sphere having completely opened the obstructed vein.

FIG. 25D is a cross section view of the magnetically-enabledthrombectomy sphere being removed by a small magnet on a guide wire.

FIG. 26A is a cross section view of the tethered magnetically-enabledthrombectomy sphere having completely opened the obstructed vein.

FIG. 26B is a tether embodiment which runs through the magnet'srotational axis.

FIG. 26C is a second tether embodiment which loops around the magnet'srotational axis.

FIG. 27 is a cross section view of a rotating magnetically-enabledthrombectomy sphere in circular motion against plaque on the vesselwalls.

FIG. 28A exhibits the result of end over end motion of a magnetic rod ormagnetic ball “walk” along a path to a distant clot in a complex vesselas imaged by an imaging technology.

FIG. 28B exhibits the ability to recreate the path based on themeasurements made in FIG. 28A.

FIGS. 29A and 29B show the clearance of a thrombosis in the vein of arabbit using the magnetomotive stator system and magnetic nanoparticles.

FIG. 30 illustrates the dosage response curve of tPA using themagnetomotive stator system showing both reduced time to increase bloodflow in a rabbit, and reduced amount of tPA required to produce the sameresult.

DETAILED DESCRIPTION Abbreviations and Definitions

Unless otherwise defined, scientific and technical terms used inconnection with the present invention shall have the meanings that arecommonly understood by those of ordinary skill in the art. Further,unless otherwise required by context, singular terms shall includepluralities and plural terms shall include the singular. Thenomenclatures utilized in connection with, and the laboratory proceduresand techniques of medicinal and pharmaceutical chemistry describedherein are those well known and commonly used in the art. Standardtechniques are used for pharmaceutical preparation, formulation, anddelivery, and treatment of patients. Other chemistry terms herein areused according to conventional usage in the art, as exemplified by TheMcGraw-Hill Dictionary of Chemical Terms (Parker, S., Ed., McGraw-Hill,San Francisco (1985)). Other terms with respect to magnetic nanoparticledynamics herein are used according to conventional usage in the art, asexemplified in the textbook Ferrohydro-Dynamics (R. E. Rosensweig, DoverPublications, New York, (1985)).

As utilized in accordance with the present disclosure, the followingterms, unless otherwise indicated, shall be understood to have thefollowing meanings:

Patient: As used herein, the term patient includes human and veterinarysubjects.

Thrombolytic drug: As used herein, a “thrombolytic drug” includes tissueplasminogen activator (tPA), plasminogen, streptokinase, urokinase,recombinant tissue plasminogen activators (rtPA), alteplase, reteplase,tenecteplase, and other drugs capable of degrading a blood clot orarteriosclerotic plaque. The term “thrombolytic drugs” includes thedrugs above alone or co-administered with warfarin and/or heparin.

Magnetic Nanoparticle: As used herein, the term “magnetic nanoparticle”refers to a coated or uncoated metal particle having a diameter betweenabout 1 nm to about 1000 nm, including about 10 nm to about 200 nm, andabout 15 nm to about 150 nm, and about 20 nm to about 60 nm, and allintegers between 1 and 1000, e.g., 1, 2, 3, 4, 5, . . . 997, 998, 999,and 1000. One of skill in the art can determine appropriate sizes ofmagnetic nanoparticles depending on the therapeutic target of thesystem, e.g., very small vessels can accept smaller nanoparticles andlarger parts of a circulatory system can accept larger nanoparticles.Examples of such magnetic nanoparticles include superparamagnetic ironoxide nanoparticles. The particles may be made of magnetite and,optionally, be coated with any one or a combination of the followingmaterials: (1) coatings which enhance the behavior of the particles inblood by making them either hydrophilic or hydrophobic; (2) coatingswhich buffer the particles which optimize the magnetic interaction andbehavior of the magnetic particles; (3) contrast agent or agents whichallow visualization with magnetic resonance imaging, X-ray, PositronEmission Tomography (PET), or ultrasound technologies; (4) drugs whichaccelerate destruction of a circulatory system blockage; and (5)thrombolytic drugs. Examples of both coated and uncoated magneticnanoparticles and methods of making such magnetic nanoparticles are wellknown in the art, for example those described in U.S. Pat. Nos.5,543,158, 5,665,277, 7,052,777, 7,329,638, 7,459,145, and 7,524,630.See also Gupta et al., Biomaterials, Volume 26, Issue 18, Jun. 2005,Pages 3995-4021. Those of skill in the art will recognize many othercombinations of features that can be included in magnetic nanoparticlesuseful in the present invention while retaining the magnetic propertiesfor use in the present invention.

Fluid Obstruction: As used herein, the term “fluid obstruction” means ablockage, either partial or complete, that impedes the normal flow offluid through a circulatory system, including the venous system,arterial system, central nervous system, and lymphatic system. Vascularocclusions are fluid obstructions that include, but are not limited to,atherosclerotic plaques, fatty buildup, arterial stenosis, restenosis,vein thrombi, cerebral thrombi, embolisms, hemorrhages, other bloodclots, and very small vessels. Sometimes, fluid obstructions aregenerally referred to as “clots”.

Substantially Clear: As used herein, the term “substantially clear”means removal of all or part of a fluid obstruction that results inincreased flow of fluid through the circulatory system. For example,creating a pathway through or around a thrombus that blocks a vein sothat blood can flow through or around the thrombus “substantiallyclears” the vein.

Very Small Vessel: As used herein, the term “very small vessel” means acirculatory system fluid pathway having a diameter from about 1 μm toabout 10 μm.

Increased Fluid Flow: As used herein, the term “increased fluid flow”means increasing the throughput of a blocked circulatory system fromzero to something greater than zero. In flowing circulatory systems, theterm “increased fluid flow” means increasing the throughput from a levelprior to administration of a magnetic nanoparticle in a patient to alevel greater than that original fluid flow level.

Agglomerate: As used herein, the term “agglomerate” means rotationalclustering and chaining of a group of individual magnetic rotors in amanner to develop “rods” from the magnetic nanoparticles as describedherein with respect to FIG. 15. Such a group of rotating rotors forms anensemble in which each individual rotor generally rotates simultaneouslyand travels in the same direction as a group. The application of thecombined field and gradient over time is the manner of assembling therods. Such a group comprises characteristics different than what can beexpected of individual rotors acting alone and creates hydrodynamicforces in a fluid stream or still fluid to create turbulence or enhancethe diffusion of a composition or liquid in the fluid stream or stillfluid.

Treatment: As used herein, “treatment” is an approach for obtainingbeneficial or desired clinical results. For purposes of this invention,beneficial or desired clinical results include, but are not limited to,one or more of the following: improvement or alleviation of any aspectof fluid obstruction in the circulatory system including, but notlimited to, fluid obstructions (e.g., stroke, deep vein thrombosis),coronary artery disease, ischemic heart disease, atherosclerosis, andhigh blood pressure.

Drug, Compound, or Pharmaceutical Composition: As used herein, the terms“pharmaceutical composition,” “compound,” or “drug” refer to a chemicalcompound or composition capable of inducing a desired therapeutic effectwhen properly administered to a patient, for example enzymaticdegradation of a thrombus or atherosclerotic plaque.

Effective Amount: An “effective amount” of drug, compound, orpharmaceutical composition is an amount sufficient to effect beneficialor desired results including clinical results such as alleviation orreduction in circulatory system fluid blockage. An effective amount canbe administered in one or more administrations. For purposes of thisinvention, an effective amount of drug, compound, or pharmaceuticalcomposition is an amount sufficient to treat (which includes toameliorate, reducing incidence of, delay and/or prevent) fluid blockagein the circulatory system, including vascular occlusions in the head andextremities. The effective amount of a drug includes coated or uncoatedmagnetic nanoparticles formulated to be administered to a patient. Theeffective amount can also include a drug, compound, or pharmaceuticalcomposition such as thrombolytic drugs. Thus, an “effective amount” maybe considered in the context of administering one or more therapeuticagents, and a single agent may be considered to be given in an effectiveamount if, in conjunction with one or more other agents, a desirableresult may be or is achieved.

Reducing Incidence: As used herein, the term “reducing incidence” offluid blockage in the circulatory system means any of reducing severity(which can include reducing need for and/or amount of (e.g., exposureto) drugs and/or therapies generally used for these conditions,including, for example, tPA), duration, and/or frequency (including, forexample, delaying or increasing time to displaying symptoms ofcirculatory system blockage). As is understood by those skilled in theart, individuals may vary in terms of their response to treatment, and,as such, for example, a “method of reducing incidence of fluid blockage”in an patient reflects administering the effective amount of themagnetic nanoparticles, whether or not in combination with a drug,compound, or pharmaceutical composition, based on a reasonableexpectation that such administration may likely cause such a reductionin incidence in that particular individual.

Ameliorating: As used herein, the term “ameliorating” one or moresymptoms of circulatory system blockage means a lessening or improvementof one or more symptoms of circulatory system blockage as compared tonot administering a magnetic nanoparticle, whether or not in combinationwith a drug, compound, or pharmaceutical composition, using the systemdescribed herein. “Ameliorating” also includes shortening or reductionin duration of a symptom.

Delaying: As used therein, “delaying” the development of a symptomrelated to circulatory system blockage means to defer, hinder, slow,retard, stabilize, and/or postpone progression of the related symptoms.This delay can be of varying lengths of time, depending on the historyof the disease and/or individuals being treated. As is evident to oneskilled in the art, a sufficient or significant delay can, in effect,encompass prevention in that the individual does not develop symptomsassociated with circulatory system blockage. A method that “delays”development of the symptom is a method that reduces probability ofdeveloping the symptom in a given time frame and/or reduces extent ofthe symptoms in a given time frame, when compared to not using themethod. Such comparisons are typically based on clinical studies, usinga statistically significant number of subjects.

Pharmaceutically Acceptable Carrier: As used herein, “pharmaceuticallyacceptable carrier” includes any material which, when combined with amagnetic nanoparticle and/or an active ingredient, is non-reactive withthe subject's immune system and allows the active ingredient to retainbiological activity. Examples include, but are not limited to, any ofthe standard pharmaceutical carriers such as a phosphate buffered salinesolution, water, emulsions such as oil/water emulsion, and various typesof wetting agents. Exemplary diluents for parenteral administration arephosphate buffered saline or normal (0.9%) saline. Compositionscomprising such carriers are formulated by well known conventionalmethods (see, for example, Remington's Pharmaceutical Sciences, 18thedition, A. Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990; andRemington, The Science and Practice of Pharmacy 20th Ed. MackPublishing, 2000).

Pharmaceutically Acceptable: The terms “pharmaceutically acceptable” asused herein means approved by a regulatory agency of the Federal or astate government or listed in the U.S. Pharmacopoeia, other generallyrecognized pharmacopoeia in addition to other formulations that are safefor use in animals, and more particularly in humans and/or non-humanmammals.

Magnetomotive Stator System and Methods for Wireless Control of MagneticRotors

This present invention relates to a system and methods for the physicalmanipulation of free magnetic rotors using a remotely placed magneticfield-generating stator. In particular, the invention relates to thecontrol of magnetic nanoparticles to increase contact of a therapeutictarget in a circulatory system with a pharmaceutical compound which canresult in increased fluid flow and the substantial clearance of fluidblockages of the circulatory system. In various aspects, the systemenhances diffusion of thrombolytic drugs and uses permanent magnet-basedor electromagnetic field-generating stator sources. Magnetic fields andgradients are used to act on magnetic nanoparticle agglomerates andmagnetic thrombectomy devices to reduce circulatory system blockages,including vascular occlusions, in a patient. In various aspects, thesystem and methods of the present invention can be used to treat fluidblockages of the circulatory system in the head (in particular, thebrain) and in the extremities of the body, such as the vasculature ofarms and legs.

The present invention consists of a magnetically produced scouringprocess generated by magnetic particles and/or magnetically-enabledthrombectomy devices acting on fluid blockage in combination with themechanically enhanced dissolving process of the thrombolytic agent thatis used. The magnetic actions are derived from a rotating magnetic fieldfrom an external source which also provides a pulling magnetic gradientthat is not rotating. This provides forces and actions on circulatorysystem blockages generally without mechanical invasion of the location.The system and methods of the present invention greatly increase druginteraction with the target circulatory system blockage, and can leaveresidue that may be collected magnetically, and also which in theprocess does not damage venous walls or valves. Another feature of thepresent invention is the ability to use drug and stirring conditions sothat essentially all of the residue that is removed forms a small softclump with the nanoparticles that can easily be captured by a tinymagnet on the tip of a guide wire. To achieve these qualities thepresent invention uses a rotating magnetic field in combination with adirected magnetic gradient to act on magnetic nanoparticles ormagnetically-enabled fluid blockage clearing devices.

In one aspect, the rotating field is generated by mechanically rotatinga strong permanent magnet having an orientation that rotates the fieldat the target site, and at the same time presents a steady magneticgradient in a desired direction. In another aspect, two or more magneticcoils can be used with appropriate phasing to provide rotating fieldswith the gradient. When three or more coils are used, at least two coilscan have axes having some perpendicular component on each other toprovide additional magnetic spatial and timing features. For instance,two coils can have perpendicular axes and one can employ current laggingthe other by 90 degrees to create a rotating field at the targetposition. A third coil can be located and oriented to provideappropriate gradients at the target site, as well as independentfunctions such as modulation.

With electronic controls of the currents, a wide array of fields andgradients can be applied with a large number of time-related events. Theresult of the basic rotating field with gradient applied to a slurry ofnanoparticles is to provide a very specific type of arrangement of thegrouping: that is the “agglomeration” of magnetic nanoparticles that inthe system and methods of the present invention cause them to formaligned rods of approximately 2 mm in length or less.

A field of about 0.02 Tesla at the target site, in combination with agradient of about 0.4 Tesla/meter, will create the desired agglomerationof magnetic nanoparticles—separated nanoparticle rods of length varyingapproximately from one to two millimeters in length. These agglomeratesremain largely intact in vitro and in vivo, but are sufficientlyflexible to provide “soft brushing” when rotated. It has been observedthat on rotation these rods “walk” along a surface in a vessel, and whenin contact with a fluid blockage, such as a blood clot, remove minuteparticles of the clot material with the aid of the thrombolytic drug.They softly “scrub” off fractions of the clot material continuously, insome cases without residue components of significant size. In othercases, depending on the type and location of obstruction, the deliveryof thrombolytic drugs can be timed so that the residue ends up in a softsmall magnetic ball, which can be captured magnetically and removed.Ultrasound and other imaging technologies can be used to visualize theprogress of such scrubbing, for example transcranial ultrasound could beused to confirm clot destruction visually in a cranial embolism orstroke. The use of contrast agents and other agents that enhancevisualization of the magnetic nanoparticles are well known in the art.

Using the same rotating magnetic field and gradient apparatus, it hasbeen observed that similar fields of 0.02 Tesla with gradients of 0.4Tesla/meter at the target site allow precise control over the rotationof a small magnetic ball approximately 1.5 mm in diameter. It has beenfound that with proper alignment of the magnetic gradient, the ball-likestructure can be made to navigate the vessels and increase drug mixingat the blockage. In a similar manner, coatings that comprisethrombolytic agents and/or surface features can be added to enhancedestruction of a blockage.

The numerical details of this process can vary, depending on theparticular nature of the circulatory system blockage, the thrombolyticdrug, and the design of the magnetically-enabled thrombectomy devices.Rotational frequencies (from about 1 to about 30 Hz, including fromabout 3 to about 10 Hz) are effective with a range of magnetic fieldmagnitudes that can be generated by magnets (from about 0.01 to about0.1 Tesla), all in a volume of about one cubic foot, or by coils withsomewhat larger volume. Gradient strength can be in a range from about0.01 Tesla/m to about 5 Tesla/m. The gradient direction generallycenters on the center of mass for a permanent magnet, and using anelectromagnet can center on one of the coils, and in combination, cancenter between one or more of the coils.

Fluid Blockages of the Circulatory System

Parts of the body where fluid blockages of the circulatory system occurinclude the legs and the brain. Two major hydrodynamic properties ofsuch blockage are observed in the vasculature: low blood flow or totalblockage. In either case, existing modes of delivery of drugs fordissolving occlusions at surfaces or mechanical removal of, for example,thrombus material cannot effectively clear a degraded and impeding layeron a clot surface to be removed to allow fresh drug interaction with anunderlayer. This often results in dangerous components moving downstreamwhich can result in a more dangerous blockage or death. In a typicalflow situation, there are locations where the flow does not effectivelypenetrate or target the intended site. In other situations it is notpossible to navigate a thrombectomy device to the target due tosmallness (e.g., a very small vessel) or complexity of thethree-dimensional shape of the occluded vessel.

Different thrombolytic drugs have been used in the thrombolytic process.For example, streptokinase is used in some cases of myocardialinfarction and pulmonary embolism. Urokinase has been used in treatingsevere or massive deep venous thrombosis, pulmonary embolism, myocardialinfarction and occluded intravenous or dialysis cannulas. TissuePlasminogen Activator (“tPA” or “PLAT”) is used clinically to treatstroke. Reteplase is used to treat heart attacks by breaking up theocclusions that cause them. In the case of thrombectomy devices,products are manufactured by several companies and employ a range oftechnologies, including mechanical extraction (Arrow International,Inc., Edward Lifesciences), venturi jet-based mechanism (BostonScientific, Possis Medical, Inc.), low-power acoustic (OmniSonicsMedical Technologies, Inc.), and abrasion and aspiration (ev3).

In the case of stroke, tPA is used successfully in many cases, but inmany cases the effect of the drug is to leave downstream residue inclumps large enough to cause further blockage and sometimes death. Inaddition, the normal thrombolytic dosage administered to patients isrelated to increased bleeding in the brain. In most cases, theeffectiveness of chemical interaction of the thrombolytic agent with theblockage is slow and inefficient, leaving incomplete removal of theblockage. In blockages in the extremities, mechanical means of stirringand guiding the drug are limited, often difficult, and can be dangerous.In another difficult issue, venous valves in the region of the procedureare damaged or not made blockage free in procedures currently used. Thepresent invention provides new systems and methods for significantimprovement in dealing with these major obstacles in treating occlusionsof the blood flow.

Magnetomotive Stator System

A therapeutic system is provided comprising (a) a magnet having amagnetic field and a gradient for controlling magnetic rotors in acirculatory system, and (b) a controller for positioning and rotatingthe field and the gradient in a manner to agglomerate and traverse themagnetic rotors with respect to a therapeutic target in the circulatorysystem. Using the therapeutic system, contact of the therapeutic targetwith a pharmaceutical composition in the circulatory system isincreased. In various aspects, the pharmaceutical composition can beattached to the magnetic rotor, and in other aspects can be administeredto the circulatory system separate from the magnetic rotors. In certaininstances, the pharmaceutical composition can be a thrombolytic drug.

Therapeutic targets of the system can include fluid obstructions such asatherosclerotic plaques, fibrous caps, fatty buildup, coronaryocclusions, arterial stenosis, arterial restenosis, vein thrombi,arterial thrombi, cerebral thrombi, embolism, hemorrhage and very smallvessels. In various aspects, the circulatory system is vasculature of apatient, in particular a human patient.

In various embodiments, the therapeutic system comprises a permanentmagnet coupled to a motor, and the controller controls a motor toposition the magnet at an effective distance, an effective plane withrespect to the therapeutic target, and rotates the magnet at aneffective frequency with respect to the therapeutic target. In variousembodiments, the therapeutic system comprises an electromagnet having amagnetic field strength and magnetic field polarization driven byelectrical current, and the controller positions the electromagnet at aneffective distance, an effective plane with respect to the therapeutictarget, and rotates the magnetic field of the electro-magnet byadjusting the electrical current.

The therapeutic system can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, such that a user controls the magneticrotors to clear the therapeutic target by adjusting a frequency of therotating magnetic field, a plane of the rotating magnetic field withrespect to the therapeutic target, and a distance of the rotatingmagnetic field with respect to the therapeutic target. In variousaspects, the therapeutic target can be a thrombosis in a human bloodvessel. In various aspects, the magnetic rotors can be magneticnanoparticles injected into the circulatory system.

In various aspects of the invention, the magnetic rotors traversethrough the fluid in the circular motion by repeatedly (a) walking endover end along the blood vessel away from the magnetic field in responseto the rotation of the rotors and an attractive force of the magneticfield, and (b) flowing back through the fluid towards the magnetic fieldin response to the rotation of the rotors and the attractive force ofthe magnetic field.

In various aspects, the obstruction to be treated using the system is athrombosis in a human blood vessel, and the magnetic rotors are formedby magnetic nanoparticles injected into the circulatory system. In thesystem, the magnetic rotors can traverse through the fluid in thecircular motion by repeatedly (a) walking end over end along the bloodvessel away from the magnetic field in response to the rotation of therotors and an attractive force of the magnetic field, and (b) flowingback through the fluid towards the magnetic field in response to therotation of the rotors and the attractive force of the magnetic field.

In another embodiment, a system is provided for increasing fluid flow ina circulatory system comprising a magnet having a magnetic field forcontrolling magnetic rotors in the fluid, a display for displaying, to auser, the magnetic rotors and the therapeutic target in the fluid, and acontroller, in response to instructions from the user, controlling themagnetic field to: (a) position the magnetic rotors adjacent to thetherapeutic target, (b) adjust an angular orientation of the magneticrotors with respect to the therapeutic target, and (c) rotate andtraverse the magnetic rotors through the fluid in a circular motion tomix the fluid and substantially clear the therapeutic target.

In various aspects, the display can display real time video of themagnetic rotors and the therapeutic target, and the display cansuperimpose a graphic representative of a rotation plane of the magneticfield and another graphic representative of the attractive force of themagnetic field on the real time video. In another aspect, the magnet canbe a permanent magnet coupled to a motor and a movable arm, and thecontroller can include a remote control device for a user to manipulatethe position, rotation plane and rotation frequency of the magneticfield with respect to the therapeutic target.

In another aspect, the display can adjust the graphics in response toinstructions given by the user through the remote control device. Invarious aspects, the magnet can be an electro-magnet coupled to a motorand a movable arm, and the controller can perform image processing toidentify the location, shape, thickness and density of the therapeutictarget, and automatically manipulates the movable arm to control theposition, rotation plane and rotation frequency of the magnetic field toclear the therapeutic target.

In yet another aspect, the magnetic rotors can be formed by magneticnanoparticles which combine in the presence of the magnetic field. Inanother aspect, the fluid can be a mixture of blood and a thrombolyticdrug, the blood and thrombolytic drug being mixed by the circular motionof the magnetic rotors to erode and clear the therapeutic target. In yetanother aspect, the circular motion of the magnetic rotors can redirectthe thrombolytic drug from a high flow blood vessel to a low flow bloodvessel which contains the therapeutic target.

One embodiment of such a magnetomotive stator system is illustrated inFIG. 1A (isometric view) and FIG. 1B (cross-section view). The operationof components is shown for this system involving rotation about a singleaxis 132. The permanent magnet cube 102 possesses a North 104 and aSouth 106 magnetic pole. The permanent magnet 102 illustrated heremeasures 3.5 inches on each side. Note that the permanent magnet 102 maybe composed of a number of permanent magnet materials, includingNeodymium-Boron-Iron and Samarium-Cobalt magnetic materials, and may bemade much bigger or smaller. The shape of the permanent magnet 102 doesnot need to be a cube. Other configurations of the permanent magneticmaterial are better in shaping the field so that aspects of the magneticfield and gradient are optimized in terms of strength and direction. Inother embodiments, the permanent magnetic material may be configured ina way to make the system more compact. A cylinder composed of permanentmagnetic material is one such example. However, simple rectangular andcubical geometries tend to be cheaper.

The face of the permanent magnet 102 in which the North 104 and South106 poles reside is glued or otherwise fastened to a mounting plate 108.The mounting plate can be composed either of magnetic or of nonmagneticmaterial. Optionally magnetic materials can be used to strengthen themagnetic field for some configurations of the permanent magneticmaterial. However, nonmagnetic mounting plates are easier to affix tothe permanent magnet 102.

This mounting plate 108 is attached to a flange 110 which passes througha first bearing 112 and a second bearing 114, both of which aresupported by the bearing mounting structure 116. Most standard bearingsare at least partially magnetic. In these cases, the flange 110 shouldbe constructed from a nonmagnetic material to ensure the magnetic fielddoes not travel efficiently from the flange 110 into the bearings 112and 114. If this were to happen, the bearings would encounter morefriction due to the magnetic attraction of the flange 110 to thebearings 112 and 114.

The end of the flange 110 is connected to a coupling 118, which connectsto a drive motor 120. The motor may be a DC or an AC motor. A highdegree of precision is capable with a servo motor, although these motorstend to cost more. In some cases, a step-down gearbox may be necessaryto spin the permanent magnet 102 at the desired frequency, given thatmost motors typically spin faster than is desired for the wirelesscontrol of magnetic rotors as used in the present invention.

The drive motor 120 is attached to a motor support structure 122 whichaffixes the drive motor 120 to a platform 124. Attached to the platform124 is a suspension mounting bracket 126 (located but not shown in FIG.1B), which is connected to a suspension arm 128. The suspension arm 128possesses an attachment joint 130. The suspension arm 128 may besuspended from overhead, from the side, or from the bottom, depending onthe best placement of the magnet stator system.

Operation of the Magnetomotive Stator System

The magnetomotive stator system (shown in FIG. 6, 602) can be positionedby the use of a portable support base 202 as shown in FIG. 2. Once inplace, and as shown in FIG. 6, a computer control panel 604 with acomputer display 606 and user control buttons 608 are used to specifythe orientation of the magnetic rotation plane 616 at the user-definedpoint in space 610. The field and gradient are manipulated in thephysical space 610. The rotation plane's normal vector 614 is specifiedby the user in the global coordinate system 612 at the point in space610, using either the control button 608 or a handheld controller 622.Within the magnetic rotation plane 616 is the initial orientation of themagnetic field 618, which may be set automatically by the computer. Theuser specifies the direction of the magnetic field rotation 620 in themagnetic rotation plane 616.

The computer process is illustrated in FIG. 7. The identification of thepoint in space 610 corresponds to 702 in the algorithm. Likewise, thespecification of the rotation plane's normal vector 614 corresponds to704 in the algorithm. Using a right-handed coordinate system, the fieldrotates clockwise around the normal vector 614. The computerautomatically sets the initial direction of the magnetic field 618,which is illustrated in the computer algorithm as 706. The user sets thefrequency of field rotation 708 within the magnetic rotation plane 616.The strength of the magnetic gradient is calculated 710 as is thestrength of the magnetic field 712. From these data, the controlparameters are calculated for the magnet system 714. For a permanentmagnet system, the control parameters correspond to the rotation speedof the drive motor(s). For an electromagnet system, the controlparameters describe the change in current in time. Once calculated, themagnetomotive stator system is turned on 716. If it is desired that themagnetic rotation plane 616 be changed, which is depicted in step 718 ofFIG. 7, the algorithm loops to the input for the rotation plane's normalvector 614, which corresponds to 704 in the algorithm.

Assuming the magnetomotive stator system of FIG. 1A is attached to theportable support base 202, the platform 124 may be oriented by the userthrough the suspension mounting brackets 126 which are attached to thesuspension arm 128, which is itself attached to the suspension armattachment joint 130. The suspension arm attachment joint 130 connectsto the arm positioner which connects to the portable support base 202.The suspension arm attachment joint 130 allows rotation of the magnetsystem about the end of the arm positioner. The suspension armattachment joint 130 also allows the platform base 124 to be rotated inthe plane perpendicular to that allowed by the suspension arm attachmentjoint 130. The motor 120, which is attached to the platform base 124 viathe motor support structure 122, spins at the desired frequency. Thismotion is coupled to the mounting flange 110 via the drive coupling 118.The first bearing 112 and the second bearing 114 allow for the mountingflange 110 to rotate smoothly. These bearings are affixed to theplatform 124 via the bearing mounting structure 116. The spinning flange110 is rigidly attached to the magnet mounting plate 108, which isattached to the permanent magnet 102. Thus, the motor 120 spin istransmitted to the permanent magnet 102. The location of the Northmagnetic pole 104 and the South magnetic pole 106 at the ends of thepermanent magnet 106, results in the desired magnetic field rotationplane 616. In this magnetic field rotation plane 616, the magnetic fieldrotates parallel to the front face of the magnet for all points locatedon the central drive axis 132.

For the manipulation of magnetic particles within the body, theuser-defined point in space 610 may be inside the head 624 for ischemicstroke therapies in which magnetite particles are manipulated to rapidlyand safely destroy clots. Likewise, the user-defined point in space 610may be inside the leg 626 for deep-vein thrombosis therapies in whichmagnetite particles are manipulated to rapidly and safely destroy clots.

In the example of magnetic particle manipulation, the magnetic particle802, which possesses a particle North magnetic pole 804 and a particleSouth magnetic pole 806, is rotated by the clockwise rotatingmagnetomotive-generated magnetic field 812 relative to the particlereference coordinate system 808. This results in the magnetic particlespinning in the direction of the clockwise rotation angle 810. When amagnetic gradient 814 is applied and a surface 816 is present, theclockwise rotating magnetomotive-generated magnetic field 812 results intraction against the surface, resulting in translation 818 to the right.

In the presence of a fluid 820 contained within an enclosing region 822,the manipulation of the magnetic particles when combined with themagnetic gradient 814 results in circulating fluid motion 824. When usedto destroy vessel obstructions 830 within a blood vessel 828, whichcontains blood 826, the magnetomotive-generated mixing results in bettermixing of the clot-busting (thrombolytic) drug. This allows for thethrombolytic dose to be lowered which, by reducing the bleedingassociated with higher doses of thrombolytic drugs, results in a saferprocedure. It also speeds the thrombolytic process.

Therefore, methods are also provided for increasing fluid flow in acirculatory system comprising: (a) administering a therapeuticallyeffective amount of magnetic rotors to the circulatory system of apatient in need thereof, and (b) applying a magnet to the patient, themagnet having a magnetic field and a gradient for controlling themagnetic rotors in a circulatory system, and (c) using a controller forpositioning and rotating the field and the gradient in a manner toagglomerate and traverse the magnetic rotors with respect to atherapeutic target in the circulatory system of the patient, whereincontact of the therapeutic target with a pharmaceutical composition inthe circulatory system is increased and fluid flow is increased.

In various aspects, the pharmaceutical composition can be attached tothe magnetic rotor. In other aspects, the pharmaceutical composition canbe administered to the circulatory system of the patient separate fromthe magnetic rotors. In various embodiments, the pharmaceuticalcomposition is a thrombolytic drug.

In various aspects, therapeutic target can be a fluid obstruction suchas atherosclerotic plaques, fibrous caps, fatty buildup, coronaryocclusions, arterial stenosis, arterial restenosis, vein thrombi,arterial thrombi, cerebral thrombi, embolism, hemorrhage and very smallvessel. In yet another aspect, the circulatory system is vasculature ofa patient, particularly a human patient.

In yet another aspect, the magnet can be a permanent magnet coupled to amotor, and the controller can control a motor to position the magnet atan effective distance, an effective plane with respect to thetherapeutic target, and rotates the magnet at an effective frequency. Inanother aspect, the magnet can be an electromagnet having a magneticfield strength and magnetic field polarization driven by electricalcurrent, and the controller can position the electromagnet at aneffective distance, an effective plane with respect to the therapeutictarget, and rotates the magnetic field of the electro-magnet byadjusting the electrical current.

The system of the method can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, wherein a user controls the magneticrotors to increase contact of the therapeutic target with apharmaceutical composition in the circulatory system by adjusting afrequency of the rotating magnetic field, a plane of the rotatingmagnetic field with respect to the therapeutic target, and a distance ofthe rotating magnetic field with respect to the therapeutic target.

In various aspects, the therapeutic target can be a thrombosis in ahuman blood vessel. In another aspect, the magnetic rotors can bemagnetic nanoparticles injected into the circulatory system. Inparticular, the therapeutic target is a full or partial blockage of avein bivalve. In yet another aspect, the magnetic rotors traversethrough the fluid in the circular motion by repeatedly (a) walking endover end along the blood vessel away from the magnetic field in responseto the rotation of the rotors and an attractive force of the magneticfield, and (b) flowing back through the fluid towards the magnetic fieldin response to the rotation of the rotors and the attractive force ofthe magnetic field.

In various aspects, the rotor is a magnetic nanoparticle of a diameterfrom about 20 nm to about 60 nm. In another aspect, the therapeutictarget is a vascular occlusion in the patient head or a vascularocclusion in the patient leg.

In yet another embodiment, a method is provided for increasing drugdiffusion in a circulatory system comprising (a) administering atherapeutically effective amount of magnetic rotors to the circulatorysystem of a patient in need thereof, and (b) applying a magnet to thepatient, the magnet having a magnetic field and a gradient forcontrolling the magnetic rotors in a circulatory system, and (c) using acontroller for positioning and rotating the field and the gradient in amanner to agglomerate and traverse the magnetic rotors with respect to atherapeutic target in the circulatory system of the patient, whereindiffusion of a pharmaceutical composition in the circulatory system atthe therapeutic target is increased.

In various aspects, the pharmaceutical composition can be attached tothe magnetic rotor. In other aspects, the pharmaceutical composition canbe administered to the circulatory system of the patient separate fromthe magnetic rotors. In various embodiments, the pharmaceuticalcomposition is a thrombolytic drug.

In various aspects, therapeutic target can be a fluid obstruction suchas atherosclerotic plaques, fibrous caps, fatty buildup, coronaryocclusions, arterial stenosis, arterial restenosis, vein thrombi,arterial thrombi, cerebral thrombi, embolism, hemorrhage and very smallvessel. In yet another aspect, the circulatory system is vasculature ofa patient, particularly a human patient.

In yet another aspect, the magnet can be a permanent magnet coupled to amotor, and the controller can control a motor to position the magnet atan effective distance, an effective plane with respect to thetherapeutic target, and rotates the magnet at an effective frequency. Inanother aspect, the magnet can be an electromagnet having a magneticfield strength and magnetic field polarization driven by electricalcurrent, and the controller can position the electromagnet at aneffective distance, an effective plane with respect to the therapeutictarget, and rotates the magnetic field of the electro-magnet byadjusting the electrical current.

The system of the method can further include a display for viewing themagnetic rotors and therapeutic target, and a user interface forcontrolling the magnetic rotors, wherein a user controls the magneticrotors to increase contact of the therapeutic target with apharmaceutical composition in the circulatory system by adjusting afrequency of the rotating magnetic field, a plane of the rotatingmagnetic field with respect to the therapeutic target, and a distance ofthe rotating magnetic field with respect to the therapeutic target.

Additional Embodiments of the Magnetomotive Stator System

FIG. 3 depicts an embodiment in which the magnet is made to spin in aplane that is perpendicular to that shown in FIG. 1. Here the permanentmagnet 302, which possesses a North magnet pole 304 and a South magnetpole 306, possesses two support flanges. The first magnet flange 308passes through the first bearing 312 and the second magnet flange 310passes through the second bearing 314. The bearings are supported by amagnet support structure 316. The magnet support structure is connectedto a center shaft 318, which is supported by the support 320 for thecenter shaft. The center shaft 318 is attached to the motor mountingplate 322, to which is attached the drive motor 324. In this embodiment,the magnet drive motor sheave 326 is connected to the drive belt 328.The drive belt 328 is connected to the magnet sheave 330. The supportfor the center shaft 320 is attached to the magnet assembly supportstructure 332.

In this embodiment, the permanent magnet 302 is made to spin in theplane perpendicular to the front face so that the North magnet pole 304and South magnet pole 306 rotate in the same plane. The drive motor 324turns the motor sheave 326, which turns the drive belt 328. The drivebelt 328 then turns the magnet sheave 330, which is attached to thesecond magnet flange 310. The first magnet flange 308 and second magnetflange 310 pass through the first bearing 312 and second bearing 314,respectively. Both magnet flanges 308 and 310 are attached to thepermanent magnet 302, thus allowing the drive motor 324 to spin thepermanent magnet 302.

In FIG. 4, a permanent magnet 436 is depicted that is capable of beingrotated in any plane using a two-motor system. The magnet possesses aNorth magnet pole 438 and a South magnet pole 440. The first motor 402is attached to the central support 406 via the first motor flange 404.Attached to the first motor 402 is the first motor pulley 408. The firstmotor pulley 408 is connected to the first axle pulley 410 via the firstmotor belt 412. The first axle pulley 410 is attached to the first axle414 which passes through the first axle bearings 416. At the end of thefirst axle 414 is the first miter gear 418. Said first miter gear 418engages the second miter gear 420. The second miter gear 420 is attachedto the second miter gear axle 422, which passes through the second mitergear bearings 424. The second miter gear bearings 424 are attached tothe magnet support yoke 426. The second miter gear pulley 428 isconnected to the second miter gear axle 422. Said second miter gear axle422 is connected to the magnet pulley 430 by the magnet belt 433. Themagnet pulley 430 is attached to one of the two magnet flanges 432. Themagnet flanges 432 pass through the magnet bearings 434. A second motor442, which is attached to the central support 406 by the second motorflange 444, which possesses a second motor pulley 446. Said second motorpulley 446 is connected to the second axle pulley 448 by the secondmotor belt 450. The second axle pulley 448 is connected to the secondaxle 452, which passes through the second axle bearings 454.

In this example, the first motor 402 turns the first motor pulley 410,which transmits the rotation to the first axle pulley 410 via the firstmotor belt 412. The first axle pulley 410 turns the first axle 414,which is made free to turn using the first axle bearings 416. Turningthe first axle 414 results in the turn of the first miter gear 418,which is connected to the first axle 414. The first miter gear 418transmits the rotation to the second miter gear 420, which turns thesecond miter gear axle 422. The turn of the second miter gear axle 422is made possible using the second miter gear bearings 424. The turn ofthe second miter gear axle 422 results in a turn of the second mitergear pulley 428, which turns the magnet pulley 430 via the magnet belt433. The magnet pulley 430 turns the magnet flanges 432, which resultsin a turn of the magnet 436 around a first axis 437.

The second motor 442 turns the second motor pulley 446, which turns thesecond axle pulley 448 via the second motor belt 450. The turns of thesecond axle pulley 448 results in a turn of the second axle 452, whichis made free to rotate using the second axle bearings 454, thus allowingthe magnet 436 to be rotated around a second axis 456.

FIG. 5 is an example of a magnetomotive system comprised ofelectromagnetic coils 502. The electromagnetic coils 502 are attached toa support structure 504. Each electromagnetic coil 502 is connected to apower supply 506 via a power supply cable 508 and power supply returncable 510. The support structure is connected to a two-segment armpositioner 512. In this example, each power supply 506 delivers power toits respective electromagnetic coil 502 via the power supply cable 508and the power supply return cable 510. The two-segment arm positioner512 allows the support structure 504 to be positioned in space.

Magnetomotive Stator System and Magnetic Tool Rotor

In yet another embodiment, a therapeutic system is provided forincreasing fluid flow in a circulatory system comprising a magnet havinga magnetic field for controlling a magnetic tool in the fluid, and acontroller positioning and rotating the magnetic field with respect tothe therapeutic target to rotate an abrasive surface of the magnetictool and maneuver the rotating abrasive surface to contact and increasefluid flow through or around the therapeutic target. In various aspects,the circulatory system can be vasculature of a patient, particularly ahuman patient. In various aspects, the magnetic tool can be coupled to astabilizing rod, and the magnetic tool rotates about the stabilizing rodin response to the rotating magnetic field. In yet another aspect, themagnetic tool can include an abrasive cap affixed to a magnet whichengages and cuts through the therapeutic target. In another aspect, thecontroller positions the magnetic tool at a target point on thetherapeutic target, and rotates the magnetic tool at a frequencysufficient to cut through the therapeutic target. The magnet can bepositioned so that poles of the magnet periodically attract the opposingpoles of the magnetic tool during rotation, the magnetic tool is pushedtowards the therapeutic target by a stabilizing rod upon which themagnetic tool rotates. In another aspect, the magnet can be positionedso that the poles of the magnet continuously attract the opposing polesof the magnetic tool during rotation, and the magnetic tool is pulledtowards the therapeutic target by an attractive force of the magnet.

FIG. 9 shows one use of the magnetomotive stator system to wirelesslymanipulate a mechanical thrombectomy device (also referred to as a“magnetic tool” above). In this example, a vessel obstruction 830 insidea blood vessel 828 is unblocked by a rotating magnet 902 which possessesa North magnet pole 904 and a South magnet pole 906 in directionstransverse to the axis 908. The magnet 902 follows the external magneticfield vector 812, which is generated wirelessly by the magnetomotivestator system. The external magnetic field vector 812 changes in time inthe direction of the magnetic field rotation angle 810. The rotation ofthe magnet 902 is stabilized by passing a stabilizing rod 908 through ahole in the magnet 902. The magnet 902 is free to rotate about thestabilizing rod 908. An abrasive cap 910 is affixed to the magnet 902which engages the vessel obstruction 830. This abrasive cap 910 may usea coating or surface treatment that ensures minimal damage to healthytissue and maximal damage to the vessel obstruction 830.

One advantage of using the magnetic tool, when larger magnetic rotorsare used, the use of the magnetic gradient, which may be time-varying,and a time-varying magnetic field allows for devices to be constructedwhich possess a magnet capable of rotating at the distal end. The resultis that these devices can be made much smaller and cheaper than existingclinical devices used to amplify the effects of pharmaceuticals or tobore through obstructions in the vasculature. More importantly,commercial technologies that use a rotation mechanism within a vessel orchamber require a mechanical or electrical transmission system from theproximal end to the distal end, which can complicate the device, makethe device more expensive, and increase the overall size. The presentinvention generates mechanical action wirelessly at the tip without theneed for the mechanical or electrical transmission system, therebyallowing the device to be smaller, simpler, and cheaper to manufacture.

FIGS. 10A and 10B illustrate an example method of use of a magnetomotivestator system and magnetic nanoparticles for the treatment of a vascularocclusion in the brain 1004, in accordance with an embodiment of theinvention. FIG. 10B shows a drip bag 1006 and an injection needle 1008coupled to a conduit or tubing inserted at an injection location 1010 ofan arm 1012 of a patient. FIG. 10A is a close-up schematic illustrationof a portion of the vasculature of the brain 1004 including a bloodvessel 828 where blood flow 1002 is unobstructed and a vessel branchhaving an obstruction 830. FIG. 10A also illustrates a rotating magneticnanoparticle (e.g., FIG. 8B) near the obstruction 830.

For example, the system may be used in a clinical setting for theenhancement of tPA which is injected intravenously. Magnetic particleswould be injected either before, after, or attached to a thrombolytic.The magnet system, which is placed close to the patient and near theclot, would be activated. However, the system would not need to begenerating a changing magnetic field at this time in that the gradientwould be sufficient to collect particles at the desired obstruction.When magnetic mixing is desired, the magnetic field would be made toalternate in time which, when combined with the magnetic gradient, whichmay or may not be varying in time, causes the action of the thrombolyticto be enhanced. Thus, the clot could be destroyed faster and better ascompared to other approaches.

Magnetically-Enhanced Drug Diffusion

FIG. 11 shows how to magnetically enable control over the diffusion of achemical injected into a moving fluidic system. In this model, fluid-Ais travelling and permeates the system (white region in FIG. 11A). At alater time, fluid-B is injected (shaded region). FIG. 11B shows theproblem. Fluid-B is limited in its ability to penetrate the “leg”because the velocity of the flow does not travel far into the leg. Thesystem then must rely on diffusion to dilute fluid-A with fluid-B. Thiscan take a very long time.

What has been observed is that when magnetic nanoparticles are placedinto fluid-B, and a magnetic field and gradient are imposed to pull someof the nanoparticles out of the stream into the leg, which take a bit offluid-B with them (FIG. 11C). Time-varying aspects can be changed toamplify the action. For example, the rate of field rotation, thestrength of the magnetic gradient, the orientation of the source field,and the size and strength of the magnetic particle. In time, moreparticles collect at the bottom of the leg and begin to set upcirculation patterns, which distribute fluid-B into fluid-A much fasterthan is possible via diffusion alone. The longer the process runs, themore particles are collected, and the stronger the mixing effectbecomes, until fluid-A is essentially replaced with fluid-B.

In the case of clot destruction, the leg represents a blocked vein orartery. As the figure depicts, to contact a thrombolytic drug to thesurface of the blockage, only the force of diffusion is involved if theobstruction is sufficiently far from the main flow. Therefore,thrombolytic drugs, and other pharmaceutical compositions effective insubstantially clearing a fluid blockage from a circulatory system, arelimited in their effectiveness; relying on diffusion in vivo couldresult in negative clinical outcomes. Because thrombolytic drugs, andpharmaceutical compositions effective in substantially clearing a fluidblockage from a circulatory system have a relatively short half-life, itis an advantage of the present magnetomotive stator system to speed theprocess. If the objective is to deliver a therapeutic concentration offluid-B at the end of the leg which is a fraction of the concentrationin the main flow, the present invention is able to obtain the sametherapeutic concentration of fluid-B for a much smaller dose of fluid-Binitially injected (See FIG. 30). This means the present inventionprovides enhanced therapeutic advantages allowing the use of a smallerdose of a pharmaceutical composition, some of which can cause bleedingor even death.

Another advantage of the present invention is, in the case of themagnetic tool, the system is capable of grinding away large volumes ofthrombus or other blockage material, such as atherosclerotic plaquematerial, quickly and very precisely. It has been observed that a 2french hole (⅔ mm) was cut through a mock atherosclerotic clot using thewireless magnetomotive stator system of the present invention. Withrespect to the use of magnetic nanoparticles in the present invention,the present system allows for precise control of magnetic particles tocreate a relatively “gentle” scouring action that allows the leaf valvesin the veins to remain intact and undamaged. With respect to themagnetic tool, this action can be used in combination with thrombolyticdrugs to remove clot material in an occluded artery or vein. When usedwith a thrombolytic in the blood clot, thrombolytic could be helpfulwhen mechanical action is intended to be minimized. Using magneticnanoparticles, the material removed from the blocked vein can becaptured with a small magnet on a guide wire. Depending on the mode ofoperation, the removed material has been observed to be small (less than1 mm size clot particles), or ball mixtures of clot material, drug andmagnetic particles. Both the magnetic particle collection and magnetictool objects are capable of being visualized with standard imagingtechnologies allowing for computer-reconstructed path planning.

FIG. 12 is a drawing of another embodiment of the magnetic fieldgenerator of this invention. In this figure, the generator 1200 iscomprised of permanent magnet source 1205 with North 1206 and South 1207poles, mounted so two separate rotations about axis 1210 and about axis1215 are enabled. For spin about axis 1210, magnet source 1205 isrotated by pulley belt 1225, which is driven by geared shaft 1226, inturn driven by driving gear 1230. Gear 1230 is mounted on thrust bearing1235 and driven by motor 1240 mounted on rotor system 1225, 1226, 1230that enables rotation about the spin axis 1210 using a motor 1245. Aseparate drive system enables rotation about second axis 1215 usingcomponents 1220, thrust bearing 1235, and motor 1240. The generator ispositioned with the jointed arm 1250. An advantage of preferredembodiment 1200 over second preferred embodiment 1300, shownschematically in FIG. 13, is the simplicity, smaller size, and lowercost. A disadvantage is the lack of some of the added features ofcontrol and complexity of the second preferred embodiment 1300.

FIG. 13 is a schematic drawing of yet another embodiment of the fieldand gradient generating device of this invention. Shown is a blockdiagram of a magnetic field generator 1300 of this invention. Threecoils, 1301, 1302, and 1303, are fed currents from drivers 1311, 1312,and 1313, through connections 1321, 1322, and 1323, respectively.Drivers 1311, 1312, and 1313 are current sources each controlledseparately by distributing circuit 1330, which receives information fromcomputer 1335. Each current source, 1311, 1312, 1313, is capable ofgenerating a sine wave current sufficient to provide the peak magneticfield required. In many cases this will be a peak field of less than 0.3Tesla. If desired in individual cases, the currents may have morecomplex temporal variations than sine waves. As determined by computer1335, in response to physician input 1341, the distribution and types ofcurrents and their sequences to each of the coils will be calculated bythe computer. The specific operational instructions from programs incomputer 1335 are based on knowledge of the particular operation, withspecific instructions thereby provided for operating according to thepresent procedure input by the physician. An advantage of the secondpreferred device 1300 of this advantage over first preferred device1200, is the added flexibility in type of fields generated from the morecomplex magnetic field sources and the computer input, and the addedrefinement to the new procedures.

The design of the circuits, power supplies and controls of generator1300 is composed of individual units to perform with these propertiesand specifications using methods that are well known to one skilled inthe field of magnetic coil design, power supplies, and computers andlogic circuitry.

Two major classes of blockage in the medical cases to be treated bymethods of this invention are partial and total. Partial blockageyields, in general, low blood flow, while total blockage will result inno blood flow. In both cases the effectiveness of a drug delivered toremove the clot by conventional means will generally be difficult andinefficient. The delivery of the drug to the surface of a clot is inprinciple difficult and inefficient in spite of special methods to stirthe drug-blood mixture near a clot. Major limits to present methods ofremoving the blockages include the difficulty of effective drug actionon an occlusion, the incompleteness of removal of dislodged material,damage to vessels and adverse effects of downstream components of theremoved material. FIGS. 14A and 14B exhibit the underlying physicalreasons for the difficulty and inefficiency of conventional treatmentsof a blood clot, and for which the present invention provides majorimprovement.

FIG. 14A is a cross sectional view of a typical accumulation ofoccluding material in a bend of a section of a blood vessel 1400 havingno flow, illustrating a common difficulty in using a drug for dissolvingthe material. Adjacent a vessel wall 1405 is a target region ofdeposited occluding material 1410, the “clot”, with internal boundaryedge 1415. Here the physician has introduced a drug 1425 in the vicinityof the clot. This exhibits the typical situation of a stagnant actionlayer 1430 of partially interacting material and layer 1435 of moreconcentrated but less effective drug. Layers 1430 and 1435 separate theclot from the more concentrated thrombolytic drug 1425 that had beeninjected into the vessel 1400 in that general region. Motion anddistribution of the drug can arise only from thermal agitation and slowdispersion as a means of refreshing contact between the clot and theinjected drug, which makes the action extremely slow and inefficient.Some practitioners have introduced metal stirrers, venturi flow-basedjets, and sound-based agitation technologies to increase efficiency, butthe difficulties and limitations of those methods have been documented.

FIG. 14B is a cross section view of a target occlusion 1455 formedagainst a wall 1460 of a vessel 1465 having a stiffened valve leaflet1470, with low blood flow in a region 1480 and with very low fluid(mixed blood and drug) flow at the clot surface 1457. This results inlittle interaction on the clot of a drug 1475 injected upstream into theregion 1480, without using excessive quantities of it. Traditionalapproaches, involve closing off the vessel and slowly injectingthrombolytic agent, with slow, inefficient dissolving of the clot, andthe injection of large quantities of thrombolytic drug, thus exhibitingapproximately the same difficulties of the case with a blocked vein.Some conventional treatments provide artificial mechanical, venturiflow-based, and sound-based agitation in region 1480 in attempts toenhance the efficiency of interaction at the clot surface 1485.Catheters with jets may spray thrombolytic drugs in attempts to get moreefficient dissolution of the clot. Removal of the occluding material issometimes performed by insertion of mechanical devices, withconsiderable difficulty and with danger to the valve. All of thesemethods may be helpful in some cases, but are generally of limitedeffectiveness.

FIG. 15A through 15C exhibit the underlying process of this invention inthe development of rods from magnetic nanoparticles. They show a crosssection of the sequence of structuring of coated or uncoated magneticparticles with increasing magnetic field. Increase of the field during arising part of the cycle causes more and more particles to align intolonger rods.

These are shown with zero field in FIG. 15A as nanoparticles in a randomdisposition of particles 1505, arrayed so as to be roughly evenlydistributed in space, and having a certain statistical fluctuation inposition. In FIG. 15B, when a small external magnetic field 1510 isapplied to the same group of particles, they are formed into a loosearray 1515 of short, oriented magnetic “rods”. At a certain larger field1520, depending on nanoparticle size and optional coating, shown in FIG.15C, the same particles aligned as magnetic rods 1525 have becomelonger. In this figure, it is depicted that the rods are uniform in sizealthough that is not strictly the case, nor is it necessary. Thismagnetic process can be viewed in two ways: a) the field increase fromFIG. 15A to FIG. 15B being that in a single (slow) cycle of magneticfield alternation, or b) the increase over a number of cycles as thepeak-to-peak magnitude of the field generated is increased. Depending onthe absolute scale and oscillating frequency, the actions are notreversed during a given cycle of oscillation. In general, as used in thepresent invention, the method applies magnetic fields of approximately0.02 to 0.2 Tesla, and the rods vary from 0.1 to 2 mm length, althoughother ranges may be useful.

At a certain rotating magnetic field strength and field rotationfrequency, depending on nanoparticle size and optional coating, the rodswill reach a saturation field and achieve a maximum length, developingas depicted in the graph of FIG. 16. The rod growth is not necessarilyexact, and the curve illustrates a general nature of the growth. Eachfully developed rod may contain a number of nanoparticles, as many as 10or many more, depending on their size, and the magnitude of the rotatingmagnetic field. The rods are not stiff, depending on the magnetic fieldand gradient, and on the amount of magnetite in each particle as well asthe nanoparticle size. Other materials may be attached to each particlefor chemical, magnetic, and imaging reasons. That chemical can be athrombolytic drug. The thrombolytic drug can also be injectedindependently.

FIG. 17 exhibits the geometric features of the end-over-end walk of asingle rotating rod acting from application of a rotating magnetic fieldemanating from a fixed source in space. It displays a sequence of 8positions of a single rotating rod as it rotates and walks, so as toexhibit the directions of field and pulling force of the gradient. It isto be understood that the effective magnetic moments of individualparticles are continually aligned with the local magnetic field, so thatthey maintain the interactions to retain the rod and its magneticmoment, while the field and rod are rotating, that is, maintainingalignment of the rod with the field.

Without being bound by a particular theory, and as will be discussed inthe following section in equations [1] and [2], the field B establishesa torque, but it does not exert a pulling force on the rod moment, whilethe gradient G exerts a pulling force but no turning torque on themoment. Therefore, a rotating magnet source will have a pulling gradienttowards it, shown as the downward arrows in all stages of FIG. 17.Smaller magnetic nanoparticles, generally below 150 nm diameter, actprimarily as permeable materials, which will automatically align withthe local field without the need to individually rotate in space. In anycase, they will form the rods as described above, which themselves havemoderate rigidity on the nano-scale, but are very soft in the millimeterscale of treatments of this invention. In FIG. 17, trigonometriclabeling illustrates the geometrical (angular) aspects of changingcomponents of the force and torques on the particles as related to thewalk of the rod towards the right in response to the rotating field. Inother words, the rods act approximately as fixed magnetic rods. In thefigure, the field direction in each of the 8 positions, is shown byarrows 1701, 1711, 1721, etc. as the field rotates clockwise. The rodmagnetic moments 1702, 1712, 1722, etc. follow that direction. In eachstage shown, however, the arrows 1703, 1713, 1723, etc. point downwardtowards the center of the rotating field source, according to equation[2] below. On the scale of the rod lengths, about 2 mm, the movement tothe right is small relative to the distance to the source magnet.

FIGS. 18A and 18B illustrate the development of a limit to theconcentration of magnetic rods when the source magnetic field isrotating, about a fixed position of the source magnet. The gradient,unlike the field, will always pull towards the magnetic center of thesource. The field B itself, only creates a torque τ of alignment on atiny magnetic dipole moment μτ=μB sin Φ,  [1]where Φ is the angle between the direction of the moment μ and the fieldB. A uniform field without gradient will not create a force on themoment μ. However, a gradient G will create a force F on tiny moment μaccording toF=μG cos Φ,  [2]where Φ is the angle between the direction of the moment μ and of thegradient G.

FIG. 18A shows the nature of the spatial “resolution” of the system inan open location for the rods. For a fixed location of the rotatingmagnet source, the pull towards it from the gradient will changedirection as the rods 1805, 1806 and 1807 have walked to the right. Theywill have increased distance, hence a loss of strength of the field. InFIG. 18A, as the rotating external field source will have remained atthe left shown by arrow 1810, the rod locations have moved to the rightof the fixed rotating magnet, (here below and off screen). At the stageshown here, the arrows depicting the three rods 1805, 1806, and 1807have moved far to the right from the center of the rotating sourcemagnet system. Relative to their size, and their distance to the magnetsource, this distance to the right has increased so that the fieldsource and gradient are at an angle and are reduced in magnitude. Thegradient, in the direction shown by large arrow 1810, pulls on theparticles and rods, which are driven by the traction provided accordingto the force of equation [2] at their locations. The gradient G isfalling off with distance from the source, typically by a factor betweenthe inverse cube and inverse fourth power of distance, while the fieldis falling off with distance from the source roughly as the inverse cubeof distance from the source center. In this walking they are also losingattractive gradient, needed to pull them down onto a walking surface.They ultimately lose traction. The consequence of this, shown in plotFIG. 18B illustrates the distribution of particles that has occurredwhen the angle of the gradient is changed from left to right, as aresult of the mechanism described in FIG. 18A below. This graph is for afixed location of the magnet source, and is useful in describing the“resolution” of the walking rod system. In practice the source can bemoved if desired for a long occlusion, depending on the medical strategyfor treating it.

A consequence of the action described in FIG. 18A, is that for a fixedlocation of the rotating magnet source the force reduction with distanceas the rods walk will result in a distribution of rod activityapproximately as shown in FIG. 18B, where the arrow simply points to aregion of maximum density at closest location to magnet, and representsthe position dependence of the rod walking, which is of maximum strengthwhen the rods are closest to the magnet source.

The magnetic mechanics of a single rotating rod provide the soft brushquantities of this invention according to the following calculations. Itis to be understood that these conditions apply directly only for rodbundles that have relatively sparsely attached clot material. Asdiscussed below, an extremely useful mode of operating rods in arotating field in which the clot material is allowed to become bundledwith the rods, leading to soft clumps that are stable and magneticallyremovable. Such a mode will not follow the calculations of this section.Nevertheless, the calculations of this section will show the underlyingbehavior of the rotating scouring rods when lightly loaded, and a modethat may be used in cases of small occlusion material, or cases wherethe delicacy of the procedure or size of vein may not allow clumps ofmaterial to be endured. Such cases may arise in some occlusions in thebrain.

Here, for simplicity the rods are treated as rigid. FIG. 19A is adiagram exhibiting trigonometric detail of the creation of rotationalforce and energy on the rotating rods that in turn creates turbulence toenhance drug mixing and interaction with the surface of the clot. Theelements of the action of the magnetic rotating field B are shown at agiven moment on a single rod of magnetic moment μ in a plane defined bydirections of the rod magnetic moment, and the direction of the field Bat an instant when B is directed at an angle β from the x-axis. At thisinstant the (constant) moment μ is directed at an angle θ from thex-axis. Therefore, at this instant the magnitude of the torque rgenerated on the moment μ by the external source magnet is given byτ=μB sin(β−θ),  [3]

FIG. 19B shows, in coordinates centered at the center of a symmetricalrod the angular force F(θ) exerted on the rod, which is assumed to besymmetrical. This is the practical situation when the rod size is smallcompared with the distance to the magnet source. The resulting forceF _(θ)=2μ(B/L)sin(β−θ)  [4]is generated by the field B at the ends of a rod of length L.

A drag force might be approximated from standard mechanics with angulardependence θ², that isF _(drag) =−Cθ ²  [5]where C is a proportional constant. Under that (standard) assumption,the final equation of motion for a symmetric rod ismlθ/4=2μβ/l[sin(β−θ)]−Cθ ²  [6]

Further, defining an angle α=β−θ and letting β=ωt, with ω an angularrotational frequency, then α=β−θ and therefore, α=−θ. Equation [3]becomesMlθ/4=(2μB/l)sin α−C(ω−α)²  [7]

For a constant lead angle α, this simplifies tosin α=clω ²/2μB  [8]

A maximum frequency ω_(o) that preserves a constant lead angle α isω_(o) ²=2μB/cl,  [9]where α=π/2, that is, 90 degrees.

At some angular frequency greater than ω_(o) the moment t cannot followthe field rotation and the system becomes destabilized. At much higherfrequency, the motion essentially halts, since the field leads by lessthan π/2 and for the other half of the time greater than π/2. Thus thetwo torques cancel. From this reasoning the kinetic energy will show afrequency dependence such as shown in FIG. 19C. Specifically, thekinetic energy T isT=2×(½)(m/2)(l/2)²θ²  [10]

FIG. 19C is a graph expressing this dependence of kinetic energy of therod on frequency of rotation in which the maximum energyT_(o)=(ml²/8)ω_(o) ² where ω=θ. That is, the peak rotational kineticenergy available for a single rod depends on the rod mass, length, andis quadratic in the angular velocity up to the point where the rodcannot follow the field rotation.

With the above understanding of the formation and mechanical behavior ofa rod of magnetic nanoparticles, the use of the system and methods ofthis invention as it applies most simply to medical applications can beshown. The system of nanoparticles has been found to behave (and appearvisually) as a group of flexible magnetic rods acting on occlusions inblood vessels. First, the treatment of the two characteristicproblematic cases discussed with FIGS. 14A and 14B, above, will be shownwith the introduction of rotating rods.

FIG. 20A illustrates the practical benefit of the introduction ofturbulence with spinning rods of the present invention. A portion of avessel having complete spatial blockage, shows the treatment by themethods of this invention of the problem shown with FIG. 14A, where itwas treated conventionally. FIG. 20A is a cross section view of lumen2000 with no flow, having a clot 2005, with a fresh supply ofthrombolytic drug 2010 being injected near the occlusion. Three spinningmagnetic rods 2030 (not to scale) have been shown injected along withthe fresh drug 2010, and they generate local turbulence as they arepulled in the direction 2025 of a rotating magnet source (not shownhere). With a clockwise spinning rotation, the rods are shownco-mingling with the fresh drug, and brushing the surface of the clot2005 as they move slowly to the left as the external rotating magneticfield source moves. The tiny particles of clot 2005 accumulate at theright 2035, where they will form a ball, when the rotation is continued,as shown in FIG. 21A. The situation is to be compared with that of FIG.14A, in a static application of drug that would have little mixingaction, and must depend on lengthy time for removal of the clot.

FIG. 20B is a cross section view of the upper part of a lumen 2050 inwhich the methods and device of the present invention are shown solvingthe problem of inefficient clot removal by standard methods in the caseas shown in FIG. 14B. This case might represent partial blockage in aleg artery. Here there is slowly flowing blood 2090 in the partiallyblocked lumen 2050, as was exhibited in FIG. 14B. Clot material 2058 and2062 has built up around valve leaflet 2060, stiffening it and causingthe significant but not total flow reduction. In this case the vessel2050 is not totally closed, and the reduced flow is due to the partialocclusion and rigidity of rigid valve 2060. As described in FIG. 14B theblood flow, though slow, carries off injected drug with inefficientcontact with the occluding material. In the method of the presentinvention the actions of rotating scouring rods 2055 are shown acting onclots 2058 and 2062, to greatly increase the drug contact, as well asprovide gentle scuffing on a tiny scale. Turbulent flow in regions 2080and 2085 is generated by the rotating rods 2055 whose tiny, somewhatflexible structure can work in such regions without damaging the vesselwall 2070 or valve leaf 2060. In some cases the removed magneticallyinfused material will be collected downstream by magnetic means.

When the rotation is continued under certain conditions (especially lowflow) the clot material and magnetic nanoparticles can form a magneticball, as described in FIG. 21B below. Again, without being bound by aparticular theory, it is believed that as the magnetic particlescirculate they engage the surface of the thrombus. As the thrombusbreaks into tiny pieces, the magnetic particles become encapsulated in aball-like structure that is composed of the magnetite and thrombusmaterials. This structure has several advantageous properties.

1. The object accelerates the destruction of the thrombus by increasingthe surface area of interaction and by causing more efficientcirculation of the thrombolytic drug.

2. The structure captures smaller emboli, encasing them in the ballstructure, thereby preventing them from escaping.

3. The structure will continue to break down slowly as that structure islysed by the thrombolytic drug.

4. Alternatively, the structure can be recollected with a magnet-tippeddevice, thereby capturing the larger emboli and the magnetic particles.

With appropriate rate of delivery of drug, depending on the nature andage of a clot and of magnetic rod interaction, the magnetic rod scouringprocess can be arranged to mix clot material and rods, as described, toprovide small, roughly spherical balls of clot material, combined withthe magnetic rods. Essentially those conditions are determined by therate of application and concentration of the thrombolytic drugs duringthe magnetic procedure. Physicians trained in the treatment ofocclusions will use judgment of the rate of delivery of drug in order toform the ball of optimal properties (stiffness and size) for completionof the removal.

An application of this technique is described as follows. FIG. 21A is across section view of a blood vessel 2120, totally occluded by clot2130, with no blood flow. Here magnetic rods 2122 are stirring theregion just proximal to occlusion 2130 with clockwise rotation of themagnetic field, causing circulation pattern 2135. The mixing region 2125contains a mixture of clot material, thrombolytic drug, and a smallamount of magnetic rod material.

In the cross section view of FIG. 21B, this rotational interaction inblood vessel 2120 has continued and a ball 2140 begins to form ofmaterial stripped from thrombus 2130 using captured emboli, and a smallamount of magnetic rod material.

In FIG. 21C the rotating ball 2140 has become enlarged and acceleratesthe therapy. It has opened the blocked channel in vessel 2120, leavingminor remains 2150 of occlusion material. The ball 2140 is stillrotating and held in location by the force from the gradient of therotating magnetic source (not shown).

FIG. 21D shows the means of capture and removal of completed clot ball2140. At an appropriate time, before restored blood flow has pushed thethrombus ball 2140 downstream, a magnet-tipped probe 2145 is insertedand captures the ball structure 1040 for removal by retracting themagnet probe 2145.

FIG. 22 is a cross section view of a blood vessel 2255 containing valveleaflets 2260, one of which, 2262, has occluding material 2263 that hasstiffened valve 2262 to become non-functional. Blood is flowing slowlyin the direction of arrow 2270. An external magnetic field generator,(not shown here but such as shown in FIG. 12 or FIG. 13), has generateda rotating field in this region into which rotating nanoparticle rods2275 are acting on clot deposits 2263 in the manner shown, for example,in FIG. 20B above. The magnetic rods 2275 shown may actually be membersof a large number of such rods in the space adjacent the clots 2263. Therods are flexible and can be brushed to lengths shorter than theapproximately one to two millimeters as described above, in order tofunction on the narrow corners of 2263. In laboratory tests the rods2275 have functioned to remove material in model spaces such as 2263that were approximately 2 centimeters wide and 3 millimeters deep andremoved approximately 100 cubic millimeters of thrombus material.

FIG. 23 is a cross section drawing of a small blood vessel 2300branching off a larger vessel 2305. The small vessel may be tortuous asshown, but does not hinder the walking travel such as that of a magneticrod 2310 shown approaching clot 2315, which might be a clot in a brainor otherwise. Such small clots 2315 can be scrubbed as described forother, generally larger vessels such as 2255 in FIG. 22 above. Thescrubbing can be generated to remove very small pieces of occludingmaterial with the appropriate field and gradient choices. Theseparticles may be up to a few microns in size, and will not cause furtherdownstream damage. An advantage of this method of clearing a clot suchas 2315 is that the occlusion might be total and difficult to reach byconventional existing methods, but the external rotating field will walkthe rods to the occlusion point. The thrombolytic drug may then beintroduced conventionally, if possible, at the site of the clot. At thatpoint the stirring activity of the rods 2310 will make the drug act muchfaster than a static delivery.

Although magnetic particles are sufficient to gently clear delicatestructures, it may sometimes be necessary to rapidly remove materialquickly, as is the case for ischemic stroke in which parts of the brainare starved of blood. The same principles used with magnetic particlesmay be employed with larger magnetic structures which are specificallydesigned to rapidly remove the occlusion by mechanical abrasion whilesimultaneously increasing the flow of thrombolytic drugs to theblockage. These larger magnetic structures, termed here as thrombectomydevices, may be spheres with an abrasive material bonded on the surface.They can be sub-millimeter in size up to a millimeter or more, alwayswith the consideration that removal after the particular procedure isnecessary. This technique will likely result in smaller residual embolithan is typically seen with conventional techniques. A further advantageof this method over existing procedures is the controllable magneticcharacter of the removed material. The thrombectomy device, which isdepicted as a sphere with a magnetic moment in this invention (i.e., a“magnetic ball”), may be tethered to simplify retrieval of the device.Alternatively, the device can be recovered in a manner similar to thatproposed for the magnetic particles, namely, the use of amagnetically-tipped guide wire. The ball's surface may be comprised ofany one or a combination of the following:

1. Contrast agent or agents which allow visualization with magneticresonance imaging, X-ray, PET, or ultrasound technologies.

2. Drugs which accelerate destruction of the blockage.

3. Optimized surface geometries to accelerate grinding.

4. Abrasive surfaces to accelerate grinding.

FIG. 24A illustrates elements of the basic operation of themagnetically-enabled thrombectomy device which is presented as a sphere2430 in this invention. The ball 2430 possesses a permanent magneticmoment with South 2410 and North 2420 ends. An externally appliedmagnetic field 2450 which advances in the counter-clockwise direction2440 causes the ball to rotate. If the magnetic gradient is absent, asis the case in this FIG. 24A, no traction is generated against thesurface 2460 and the ball does not translate.

FIG. 24B depicts the same case as 13A except that a magnetic gradient2480 is present in an essentially fixed given direction 2480 whichgenerates a force in the direction of 2480 acting on the magnetic ball2430 to press it against the vessel wall. As a result, traction iscreated and translational motion occurs in direction 2470 with thecounter clockwise rotation 2440 of the field.

An application of this technique is described as follows. FIG. 25A is across section view of a blood vessel 2510, totally occluded, with noblood flow. Here a magnetic ball 2530 is stirring the region justproximal to occlusion 2515 while mechanically grinding the occlusion'ssurface 2522. Contact against surface 2522 is created by a gradient indirection 2520 which results in a translational force in direction 2520.Clockwise motion of ball 2530 causes circulation pattern 2525 whichaccelerates action of the thrombolytic drug.

In the cross section view of FIG. 25B the rotational interaction inblood vessel 2510 has continued and ball 2530 has deeper penetrationinto occlusion 2515 in the translation direction 2520.

In FIG. 25C the rotating magnetically-enabled ball 2530 has opened theblocked channel 2535 in vessel 2510 leaving minor remains of occlusionmaterial 2515.

FIG. 25D shows a means of capture and removal of themagnetically-enabled ball 2530 from the vessel 2510. The external field2520 is no longer rotated or is removed which causes the ball to nolonger translate to the right. At an appropriate time, before restoredblood flow has pushed thrombectomy ball 2530 downstream, a magnet-tippedprobe 2540 is inserted and captures ball 2530 for removal by retractingmagnet probe 2540.

Cross sectional view FIG. 26A shows a tethered 2630 magnetically-enabledball 2610 in vessel 2605. The tether 2630 allows the ball 2610 to rotatewith the magnetic field, using attachments to be shown in FIG. 26B or26C. In this figure, the North 2640 and South 2645 ends of the magnetare depicted at the ends of the black arrow. A free rotation of themagnet field 2640-2645 allows grinding of the thrombus or plaquematerial 2620 inside of the vessel 2605. The tether 2630 ensures themagnet 2610 can be manually retrieved without the need of themagnetically-tipped wire 2540 that was depicted in FIG. 25D. Tether 2630will not wind on the ball 2610 under rotation when designed according tomethods and devices of FIGS. 26B and 26C.

FIG. 26B shows a first embodiment of a tether 2660 which allows rotationaround the magnet 2610 axis 2650. In this depiction, the tether end 2665is inserted through the rotational axis 2650 loosely to ensure freerotation about the axis 2650. North 2640 and South 2645 arrow depictsmagnetization direction of ball 2610.

FIG. 26C shows a second embodiment of a tether. Tether 2670 allowsrotation around the magnet 2610 axis 2650 (perpendicular to loop 2675).In this depiction, the tether is loop 2675 which loosely surrounds themagnet's axis 2650 to ensure free rotation about the axis 2650. TheNorth 2640 and South 2645 ends of arrow 2680 depict magnetizationdirection of ball 2610.

The technologies described in this invention also may be used inremoving vulnerable plaque 2715 on a vessel 2705 wall depicted in FIG.27. In FIG. 27, a cross section view of a blood vessel 2705 is shownwith vulnerable plaque 2715 on the top and bottom of the vessel 2705. Arotating magnetic ball 2710 is shown grinding the plaque 2715 in amanner similar to that used on the occlusion 2515 depicted in FIG. 25Cand the tethered depiction 2630 in FIG. 26A. This is made possible byusing an externally-generated gradient 2720 to direct the action upwardstowards the plaque 2715. It is assumed that thrombolytic drugs may alsobe present to ensure the ejected material is dissolved.

To ensure the magnetic particles and magnetically-enabled thrombectomydevice are capable of being seen with modern imaging technologies, theparticles must possess a coating which makes them opaque to that imagingtechnology. Example contrast coatings include x-ray, PET, MR andultrasound. An advantage of such coatings is the ability to reconstructa vessel which would normally be invisible due to the lack of blood flowin that region. Likewise, the ability to control and recollect theparticles results in less toxic side effects as is seen with traditionalcontrast agents. For example, X-ray contrast agents typically requiremultiple injections because they are swept away with blood flow and arenot able to travel in high concentrations down low-flow vessels.

FIG. 28A is a cross section drawing of a small blood vessel 2820branching off a larger vessel 2810. The small vessel 2820 may betortuous as shown, but does not hinder the walking travel of magneticrod collection and the rolling motion of a magnetically-enabled ball.Both technologies are depicted as starting at the right side of thesmall vessel 2820 and approaching a blockage 2815. At subsequent pointsin time, the location of the magnetic ball or magnet rod collection 2825is identified at the points indicated by 2826, 2827, 2828, and 2829. Thetranslation direction of the particle collection or magnetic ball 2825is indicated by the arrow 2830 extending from the body.

FIG. 28B is the same cross section drawing depicted in FIG. 28A. In thisview, the imaged locations of the particle collection or the magneticball are connected allowing a computer to reconstruct the path 2835.This path can be referenced against preoperative images to confirm theanatomy and to plan procedures requiring navigation along the path.

Compositions for Use in the System

Various formulations of magnetic nanoparticles, whether formulated incombination with pharmaceutical compositions or not, may be used foradministration to a patient. Those of skill in the art will recognizehow to formulate various pharmaceutical compositions, drugs andcompounds for co-administration with the magnetic nanoparticles hereof,or administration separate from the nanoparticles. Those of skill in theart will also recognize how to formulate coated nanoparticles inaddition to uncoated nanoparticles that may depend on the coating andthe therapeutic target to be treated. In some embodiments, variousformulations of the magnetic nanoparticles thereof may be administeredneat. In other embodiments, various formulations and a pharmaceuticallyacceptable carrier can be administered, and may be in variousformulations. Pharmaceutically acceptable carriers are known in the art.For example, a carrier can give form or consistency, or act as adiluent. Suitable excipients include but are not limited to stabilizingagents, wetting and emulsifying agents, salts for varying osmolarity,encapsulating agents, buffers, and skin penetration enhancers.Excipients as well as formulations for parenteral and nonparenteral drugdelivery are set forth in Remington, The Science and Practice ofPharmacy 20th Ed. Mack Publishing (2000).

In some embodiments, the magnetic nanoparticles are formulated foradministration by injection (e.g., intraperitoneally, intravenously,subcutaneously, intramuscularly, etc.), although other forms ofadministration (e.g., oral, mucosal, etc.) can be also used depending onthe circulatory system blockage to be treated. Accordingly, theformulations can be combined with pharmaceutically acceptable vehiclessuch as saline, Ringer's solution, dextrose solution, and the like. Theparticular dosage regimen, i.e., dose, timing and repetition, willdepend on the particular individual, that individual's medical history,and the circulatory system blockage to be treated. Generally, any of thefollowing doses may be used: a dose of about 1 mg/kg body weight; atleast about 750 μg/kg body weight; at least about 500 μg/kg body weight;at least about 250 μg/kg body weight; at least about 100 μg/kg bodyweight; at least about 50 μg/kg body weight; at least about 10 μg/kgbody weight; at least about 1 μg/kg body weight, or less, isadministered. Empirical considerations, such as the half-life of athrombolytic drug, generally will contribute to determination of thedosage.

Advantages of the Magnetomotive Stator System

Having described the magnetomotive stator system and methods ofcontrolling magnetic nanoparticles and other magnetic rods (e.g.,magnetic tools), several advantages can be observed when compared todevices and pharmaceutical compositions currently on the market. First,the ability to combine the magnetic gradient with the magnetic field inan advantageous way that allows for magnetic rotors to be controlledfrom a distance, as opposed to catheters and cannulae which may causeunintended injury to a patient. Second, The ability to construct acompact mechanism that allows for the magnetic field to be changed intime in a simple and precise way, as well as possibly optimized so thatcontrol over the wireless rotors, is a significant enhancement in viewof pharmaceutical compositions that are hard to precisely control invivo at normal dosages.

In addition, when the magnetic rotors consist of magnetic nanoparticles,such as magnetite, the rotors can be manipulated in a way that resultsin better mixing of a chemical or pharmaceutical agent that is in thevicinity of the magnetic particles. The use of the magnetic gradientcombined with a time-varying magnetic field allows for flow patterns tobe created which then amplifies the interaction of the chemical orpharmaceutical. This mechanism has been observed in animal models forthe destruction of clots within the endovascular system using tPA as athrombolytic. The pharmaceutical compositions can also be attached tothe magnetic nanoparticles to perform the same function. As a result,less of those agents would be required for patient treatment providedthat the particles are able to be navigated to and interact with thedesired targets using the magnetic gradient and the time-varyingmagnetic field of the system of the present invention.

The magnetomotive system can make use of an easy-to-understanduser-interface which allows the user to control the rotation plane ofthe magnetic field in a way that is not presently found.

The magnetomotive system can also be used to move particles within smallchannels in a manner superior to approaches attempted with non-varyingmagnetic fields. The combined use of the magnetic gradient with atime-varying magnetic field allows for the particles to travel intosmall vessels, at which point therapy can be directed.

The invention will be further described in the following examples, whichdo not limit the scope of the invention described in the claims.

EXAMPLES

Aspects of the present teachings may be further understood in light ofthe following examples, which should not be construed as limiting thescope of the present teachings in any way.

Example 1—Administration of Magnetic Particles to Rabbits

Anesthetized rabbits were used to create an endovascular obstructionmodel by using the jugular veins and generating a clot at this locationusing thrombin, a natural product that produces blood clots. Once astable clot was established, tPA (an enzyme commonly used to dissolveclots in endovascular obstruction patients), and magnetic nanoparticleswere directed to the clot location and time needed to dissolve the clotwas recorded. See FIG. 30. After varying time points, the animals wereeuthanized, the remaining clots were weighed and analyzed and tissueswere collected to ensure that there was no damage to the vessel itself.

The endovascular obstruction model allows the determination whether themagnetomotive stator system can re-open a vein or artery faster thanwith tPA alone, and if the dosage of tPA can be reduced the amount oftPA required without causing damage to the vein. The data gathered fromthe present endovascular obstruction studies clearly show that themagnetomotive stator system significantly speeds up the “clot-busting”activity of tPA.

Detailed Protocol

Summary: Deep Vein Thrombosis is a common and potentially deadlycondition, and current treatment options can do more harm than good insome cases. Our aim is to use a non-survival anesthetized rabbit modelof venous thrombosis to determine whether we can substantially increasethe efficiency of current pharmacological treatment by manipulatingcommonly used MRI contrast media magnetically (Magnetic particles inimaging: D. Pouliquen et. al., Iron Oxide Nanoparticles for use as anMRI contrast agent: Pharmacokinetics and metabolism; Magnetic ResonanceImaging Vol. 9, pp 275-283, 1991).

Magnetics: The iron nanoparticles described above are currently used inhumans and considered safe.

Introduction: Deep Vein thrombosis (DVT) can be asymptomatic, but inmost cases the affected areas are painful, swollen, red and engorgedsuperficial veins. Left untreated, complications can include tissuenecrosis and loss of function in the affected limb. The most seriouscomplication is that the clot could dislodge and travel to the lungsresulting in a pulmonary embolism (PE) and death. Current treatment ofDVT includes high doses of lytic enzymes such as streptokinase andtissue plasminogen activator (tPA), sometimes augmented with mechanicalextraction (Angiojet, Trellis Infusion System). The doses of lyticenzymes are such that in many patients (particularly elderly) the riskof hemorrhage is high and poor outcomes common (A review ofantithrombotics: Leadley R J Jr, Chi L, Rebello S S, Gagnon A. JPharmacol Toxicol Methods, Contribution of in vivo models of thrombosisto the discovery and development of novel antithrombotic agents, 2000Mar.-Apr., (2):101-16; A review of potential tPA complications:Hemorrhagic complications associated with the use of intravenous tissueplasminogen activator in treatment of acute myocardial infarction, TheAmerican Journal of Medicine, Volume 85, Issue 3, Pages 353-359 R.Califf, E. Topol, B. George, J. Boswick, C. Abbottsmith, K. Sigmon, R.Candela, R. Masek, D. Kereiakes, W. O'Neill, et al.). The aim of thepresent DVT model is to allow determination of whether the magnetomotivestator system enhances the activity of tPA at the site of the thrombussuch that a significantly lower dose of tPA can be used, greatlyreducing the risk of hemorrhage. Further, current mechanicalthrombolytics are known to damage endothelium. Following eachexperiment, the vessel segment is evaluated histologically forendothelial integrity.

Procedure: This is a non-survival procedure. New Zealand White rabbits(1.5-2.5 kg) are anesthetized using Ketamine 35 mg/kg, Xylazine 5 mg/kgIM and the ventral neck shaved and prepared for surgery. Mask inductionusing isoflurane gas may be used to deepen the anesthetic plane to allowfor orotracheal intubation. Once intubated, the animal is moved to theoperating room and administered isoflurane gas anesthesia (1-5%, tosurgical effect) for the duration of the procedure. Heart rate,respiratory rate, body temperature and end-tidal CO₂ are monitored whilethe animal is under anesthesia. In an effort to reduce the number ofanimals and reduce the variability among studies, bilateral 10-12 cmincisions are made paramedian to the trachea and sharp/blunt dissectionis used to isolate the jugular veins. If no significant complicationsarise, the total number of animals are reduced accordingly.

An ultrasonic flow probe is placed on the distal portion of the isolatedvessel and baseline blood flow data is collected for 30 minutes.Following stabilization of venous flow, silk (or other braided,uncoated) suture (5 or 6-0, taper needle) is passed transversely throughthe center of the vessel lumen at the distal aspect of the area to beoccluded, and secured with a loose knot (see reference #5). The functionof this suture is to act as an anchor for the clot and prevent embolism.Then, a ligature is placed on the proximal and distal portion of thevessel (proximal in relation to the flow probe) to occlude flow.Ultimately a 2 or 3 cm segment of the vessel is isolated with ligatures.100-200 U bovine thrombin is administered intravenously (27-30 g needle)into the space approximately 1 mm proximal the first ligature. Theproximal ligature is placed immediately following withdrawal of thethrombin needle. The entry site of the needle is closed with a smalldrop of Vetbond® to prevent bleeding during the lysis procedure. Theclot is allowed to mature and stabilize for 30 minutes at which time theligatures are removed and tPA or a combination of tPA with magneticnanoparticles (described above) are injected at the antegrade aspect ofthe vein (27-30 g needle, entry hole again sealed with Vetbond®). Adynamic magnetic field is applied to the location and dissolution of theclot is monitored continuously for up to 3 hours via ultrasonicflowmetry. Following re-establishment of flow the animals are euthanizedwhile still under anesthesia with an i.v. overdose of pentobarbital (150mpk). The experimental vessel segment and residual clot is thencollected, weighed and fixed for further analysis. Dosages of tPA usedin the endovascular obstruction model range from about 312.5 U to about5000 U.

Groups: The study is accomplished in 2 phases, Pilot and Proof ofConcept. Both phases include the procedures outlined here, but the PilotPhase utilize only the left jugular, leaving the other a naïvehistological comparator.

Pilot Groups

1. Thrombin only, no tPA. This group will establish the baseline mass ofour thrombus and allow assessment of thrombus stability.

n=30.

2. tPA only, dose ranging to establish a fully efficacious dose (100%re-cannulation) n=6×3 doses=18

3. tPA only, dose ranging to establish a sub-optimal dose (either 100%effective in 25-50% of subjects, or re-cannulation in all

subjects but only 25-50% of flow rate). tPA is notoriously variable, sothe sub-optimal dose may be difficult to find. n=3×4

doses=12

Device alone to establish optimum particle concentration n=3×3concentrations=9

Proof of Concept Groups:

Note: “n” numbers may be combined with pilot data depending on initialdata quality, further reducing animal requirements.

1. Optimal tPA. n=6

2. Sub-optimal tPA. n=6

3. Device alone. n=6

4. Device+Optimal tPA. n=6

5. Device+sub-optimal tPA. n=6

Two questions can be answered using the present endovascular obstructionmodel:

Small Vessels: Following the completion of the thrombosis procedure inthe jugular veins, the surgical plane of anesthesia is continued and alaparotomy performed. A portion of the bowel is exteriorized and bathedin saline to prevent drying. One of the large veins in the mesentery istied off and cannulated with PE10. A mixture of iron particles andfluorescein (12.5 mg/ml in 100 ul) is injected and photographed underblack light. This allows the determination of whether the fluoresceindiffuses into the very small veins surrounding the bowel, andillustrates that the magnetomotive stator system directs magneticnanoparticles to the small vasculature.

Safety: Is damage done to the endothelial lining using the magnetomotivestator system? Does it create hemolysis? The present endovascularobstruction model allows a determination via review of the vena cava.Following the completion of the thrombosis procedure in the jugularveins, the surgical plane of anesthesia is continued and a laparotomyperformed. A 5-6 cm segment of the vena cava is isolated and allbranches tied off. The vessel is tied off and cannulated with PE10.Either iron nanoparticles (12.5 mg/ml in 100 μl) or saline (100 μl) isinjected and the vessel and is magnetically controlled for 3 hours. Atthe end of 3 hours the blood is removed from the vessel segment viavenipuncture and sent for assessment of hemolysis. Following euthanasiathe vessel segment is explanted for histological evaluation of theendothelium. Three experiments are performed with particles and threewithout.

Arterial Access

Using the DVT model described above, it has been demonstrated that themagnetomotive stator system significantly enhances tPA efficacy in thisrabbit model. See FIGS. 29 and 30. Tissues have been gathered that wereevaluated histologically. There is no damage observed to tissue whenexamined histologically.

OTHER EMBODIMENTS

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the present invention. However, theinvention described and claimed herein is not to be limited in scope bythe specific embodiments herein disclosed because these embodiments areintended as illustration of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description which do not depart from thespirit or scope of the present inventive discovery. Such modificationsare also intended to fall within the scope of the appended claims.

REFERENCES CITED

Citation of a reference herein shall not be construed as an admissionthat such is prior art to the present invention.

What is claimed is:
 1. A method of facilitating treatment of a totalocclusion in a vessel of a subject through external magnetomotivemanipulation of magnetic particles, the method comprising: introducing aplurality of magnetic particles within vasculature of the subject,orienting a permanent magnet external to the vessel to establish amagnetic rotation plane of the permanent magnet, wherein the permanentmagnet has a magnetic field and a directed magnetic gradient;programming a controller to rotate the permanent magnet in a mannersufficient to agglomerate the magnetic particles to form a plurality ofmagnetic rods within the vasculature to travel toward the totalocclusion in the vessel in an end over end walking motion, wherein theend over end walking motion of each of the magnetic rods generates astirring motion within the vessel proximal to the total occlusion, andwherein the stirring motion facilitates contact of at least one of (i)an agent configured to facilitate visualization with an imaging modalityor (ii) a drug configured to accelerate destruction of the totalocclusion, by enhancing diffusion of the agent or the drug to a regionof the total occlusion.
 2. The method of claim 1: wherein the permanentmagnet is rotatably coupled to a motor by a movable arm, wherein thepermanent magnet is configured to rotate about two different axes ofrotation, and wherein the particles comprises magnetite.
 3. The methodof claim 1, wherein the agent or the drug is attached to the magneticparticles prior to introducing the magnetic particles.
 4. The method ofclaim 1, wherein the agent or the drug is introduced within thevasculature separate from the magnetic particles.
 5. The method of claim1, wherein the permanent magnet is rotatably coupled to a motor by amovable arm.
 6. The method of claim 1, further comprising adjusting oneor more of a position, the magnetic rotation plane, and a rotationfrequency of the permanent magnet.
 7. The method of claim 6, whereinsaid adjusting is performed in response to at least one characteristicof the total occlusion.
 8. The method of claim 7, wherein the at leastone characteristic is selected from the group consisting of: a location,a shape, a thickness, and a density of the total occlusion.
 9. Themethod of claim 7, wherein the at least one characteristic is determinedfrom one or more images of a region of the vessel in which the totalocclusion is located.
 10. The method of claim 1, wherein said orientinga permanent magnet is performed based on preoperative images of thevessel.
 11. A method of facilitating treatment of a blockage within avessel of a subject through external magnetomotive manipulation ofmagnetic particles, the method comprising: administering a plurality ofmagnetic particles within vasculature of the subject, positioning amagnet external to the vessel to establish a magnetic rotation plane ofthe magnet, wherein the magnet has a magnetic field and a directedmagnetic gradient; programming a controller to position and rotate themagnet in a manner sufficient to agglomerate the magnetic particles toform a plurality of agglomerations within the vasculature, wherein theagglomerations travel within the vasculature toward the blockage withinthe vessel in an end-over-end motion under influence of the magneticfield and the directed magnetic gradient of the magnet; wherein theend-over-end motion of each of the agglomerations generates a stirringmotion within the vessel proximal to the blockage, and wherein thestirring motion facilitates contact of at least one of (i) an agentconfigured to facilitate visualization with an imaging modality or (ii)a drug configured to accelerate destruction of the blockage, byenhancing diffusion of the agent or the drug to a region of theblockage.
 12. The method of claim 11: wherein the magnet is a permanentmagnet, wherein the permanent magnet is rotatably coupled to a motor bya movable arm, wherein the permanent magnet is configured to rotateabout two different axes of rotation, and wherein the particlescomprises magnetite.
 13. The method of claim 11, wherein the agent orthe drug is attached to the magnetic particles prior to introducing themagnetic particles.
 14. The method of claim 13, wherein the agent or thedrug is coated on the magnetic particles.
 15. The method of claim 11,wherein the agent or the drug is introduced within the vasculatureseparate from the magnetic particles.
 16. The method of claim 11,wherein the magnet is rotatably coupled to a motor by a movable arm. 17.The method of claim 11, wherein the blockage comprises a totalocclusion.
 18. The method of claim 11, wherein the agglomerationscomprise rotating rods.
 19. The method of claim 11, wherein theagglomerations comprise spheres.
 20. The method of claim 11, wherein theblockage comprises a partial blockage.